Deep Eutectic Solvents for Efficient and Selective Extraction of α-Glucosidase Inhibitors from Waste Seeds of Refined Betel Nuts.

During the production process of refined betel nuts in China, a large amount of processing by-product, betel nut waste seeds, is generated. Betel nut waste seeds are rich in bioactive elements, but they have not been effectively utilized yet. In this study, an ultrasonic-assisted deep eutectic solvent method (DES) was used to selectively extract α-glucosidase inhibitors from waste seeds. Compared with traditional extraction solvents such as water and ethanol, the extraction efficiency of specific DESs is higher, and the content of alkaloids in the extracts is lower. However, it should be noted that some pure DESs exhibit inhibitory activity towards α-glucosidase. DESs, based on choline chloride/urea, were selected due to the high extraction efficiency of α-glucosidase inhibitors and their low alkaloid content as well as low inhibitory activity. The optimal extraction conditions were determined using single-factor experiments as follows: 30% (v/v) water content, a choline chloride/urea ratio of 5:3, a solid-liquid ratio of 1:10, extraction temperature of 40 °C, and a duration of 30 min. Through recovery experiments, it was found that the DES can be reused four times under these conditions, maintaining an inhibition rate comparable to alcohol extraction methods. The IC50 value of the extract was measured at 0.0066 mg/mL, superior to acarbose. In summary, this research has successfully developed an efficient and selective method for extracting α-glucosidase inhibitors from betel nut waste seeds, thereby presenting a promising avenue for future applications.

Biological Effects and Biomedical Applications of Areca Nut and Its Extract.

The dried, mature fruit of the palm tree species Areca catechu L. is known as the areca nut (AN) or betel nut. It is widely cultivated in the tropical regions. In many nations, AN is utilized for traditional herbal treatments or social activities. AN has historically been used to address various health issues, such as diarrhea, arthritis, dyspepsia, malaria, and so on. In this review, we have conducted a comprehensive summary of the biological effects and biomedical applications of AN and its extracts. Initially, we provided an overview of the constituents in AN extract. Subsequently, we summarized the biological effects of AN and its extracts on the digestive system, nervous system, and circulatory system. And we elucidated the contributions of AN and its extracts in antidepressant, anti-inflammatory, antioxidant, and antibacterial applications. Finally, we have discussed the challenges and future perspectives regarding the utilization of AN and its extracts as emerging pharmaceuticals or valuable adjuncts within the pharmaceutical field.

Desymmetric Cyanosilylation of Acyclic 1,3-Diketones.

Diastereo- and enantioselective construction of vicinal stereocenters from easily available starting materials is a challenging task. Here, we report that a bifunctional catalyst prepared from dibutylmagnesium and a pipecolinol-derived tetradentate ligand can enable an asymmetric cyanosilylation of 1,3-diketones to forge a pair of neighboring and acyclic tetrasubstituted carbons. The high stereoselectivity results from the rigid conformation of the diketone in the catalyst pocket, where the Lewis acidic magnesium center, together with the free hydroxyl group as a putative hydrogen bond donor, bind with both carbonyls. Consequently, stereochemically well-defined cyanohydrin silyl ethers with a diverse collection of substituents were prepared. Their rapid derivatization to molecules of higher complexity, such as heterocycles, triols, and fused rings, were also demonstrated.

Paeonol attenuates heart failure induced by transverse aortic constriction via ERK1/2 signalling.

CONTEXT: Paeonol (PAE) is the main phytochemical from Cortex Moutan. Its main pharmacological effects are anti-inflammatory and antioxidant, but its cardioprotective effect is unclear. OBJECTIVE: The study investigates the effects and underlying mechanisms of PAE on transverse aortic constriction (TAC)-induced heart failure (HF) in mice. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into five groups: sham, TAC, PAE10 (TAC + PAE 10 mg/kg), PAE20 (TAC + PAE 20 mg/kg) and PAE 50 (TAC + PAE 50 mg/kg). Paeonol was intragastrically administered to mice for 4 weeks. Mice were anaesthetized with pentobarbital sodium and underwent cardiac echocardiography using echocardiography system. Serum levels of atrial natriuretic peptide (ANP), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial apoptosis was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. Haematoxylin-eosin (H&E) and Masson's staining were used for histopathological evaluation. Western and quantitative real-time PCR (qRT-PCR) were performed to detect levels of apoptosis and fibrosis-related proteins. RESULTS: Echocardiography showed PAE improved cardiac function (LVEF: TAC, 52.3±6.8%; PAE20, 65.8±3.6%; PAE50, 71.4±2.5%) and H&E staining showed PAE alleviated myocardial injury (TAC: 1170.3 ± 134.6 µm2; PAE50: 576.0 ± 53.5 µm2). Western and qRT-PCR results showed that PAE down-regulated the levels of ANP, BNP and α-MHC. In addition, TUNEL and western results showed PAE significantly inhibited apoptosis. Masson and western results showed PAE inhibited cardiac hypertrophy. Western results showed the ERK1/2/JNK pathway could be inhibited by PAE. DISCUSSION AND CONCLUSIONS: Paeonol regulates ERK1/2/JNK to improve cardiac function, which provides theoretical support for the extensive clinical treatment of HF.

Early detection of immune checkpoint inhibitor-related subclinical cardiotoxicity: A pilot study by using speckle tracking imaging and three-dimensional echocardiography.

Background: Early detection of subclinical cardiotoxicity of immune checkpoint inhibitor (ICI) therapy can be challenging. Objective: To evaluate subclinical cardiac dysfunction using two-dimensional speckle tracking imaging (2D-STI) and three-dimensional echocardiography in Chinese patients. Methods: Fifty-five consecutive patients with malignant tumors treated by immunotherapy were included. They were examined by echocardiography before immunotherapy and after immunotherapy. Left ventricular ejection fraction (LVEF) was calculated in three-dimensional imaging. Moreover, left ventricular global longitudinal peak systolic strain (LVGLS), left ventricular global circumferential peak systolic strain (LVGCS), right ventricular global longitudinal systolic strain (RVGLS), right ventricular free wall longitudinal peak systolic strain (RVFWLS), and tricuspid annular plane systolic excursion (TAPSE) were evaluated. Clinical and laboratory parameters were recorded. Cardiac toxicity events were defined as the presence of heart failure symptoms, LVEF reduction, and increase in troponin. Subclinical cardiac toxicity was defined as cardiac dysfunction associated with ICI treatment, with absent or delayed ICI-associated cardiotoxicity clinical symptoms. Results: Compared with baseline, the LVGLS, TAPSE, and RVGLS significantly deteriorated after ICI treatment [(-18.63 ± 2.53)% vs. (-17.35 ± 2.58)%, P = 0.000; 18.29 ± 6.23 vs. 14.57 ± 3.81, P = 0.0001; and (-18.45 ± 4.65)% vs. (-14.98 ± 3.85)%, P = 0.0001, respectively]. LVGLS (-17.35 ± 2.58, P = 0.000), TAPSE (14.57 ± 3.81, P = 0.0001), and RVGLS [(-14.98 ± 3.85)%, P = 0.0001] were decreased after ICI immunotherapy. Kaplan-Meier curve analysis showed that LVGLS was more sensitive than the cardiac toxicity events to assess ICI-related subclinical cardiac dysfunction (log-rank P = 0.205). The ROC curve showed that the cutoff value of ΔLVGLS was -13%. Conclusion: Subclinical cardiac dysfunction can be detected using two-dimensional speckle-tracking imaging. LVGLS, RVGLS, and TAPSE are more sensitive indices for detection. Clinical trial registration: [https://www.chictr.org.cn/showprojen.aspx?proj=27498], identifier [ChiCTR1800016216].

Dynamic Changes of Serum Heart Type-Fatty Acid Binding Protein in Cancer Patients Treated With Immune Checkpoint Inhibitors.

Objective: Immune checkpoint inhibitors (ICIs) are effective anti-cancer drugs that can improve survival in cancer patients, but their use may be associated with adverse cardiovascular side effects. Therefore, there is a clinical unmet need to identify non-invasive biomarker to detect subclinical cardiac toxicity after ICI treatment. The aim of this study is to examine the plasma levels of biomarkers in cancer survivors who were treated with ICIs. Patients and Methods: In a cohort of 19 cancer patients, biomarkers were evaluated at baseline, 1 month, 3 and 6 months after ICI administration. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included cardiac troponin I (cTnI), high-sensitivity C-reactive protein (Hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), CK (creatine kinase), CK-MB (creatine kinase-MB), Pentraxin-related protein 3 (PTX3), growth differentiation factor 15 (GDF-15), heart type-fatty acid binding protein (H-FABP) and galectin 3 (Gal-3). Results: H-FABP, but not other biomarkers, were increased at 3 months, which persisted at 6 months (529.28 ± 312.83 vs. 752.33 ± 283.65 vs. 808.00 ± 289.69 pg/ml, p = 0.031 and p = 0.013). Left ventricular ejection fraction (63.00 ± 4.15% vs. 63.74 ± 4.07%, p > 0.05) was not significantly reduced at this time point. Conclusions: H-FABP, but not other biomarkers, were increased in patients who were treated using ICIs. H-FABP might be a more sensitive biomarker to detect ICI-related subclinical myocardial damage than traditional cardiac biomarkers.

Higher Incidence of Atrial Fibrillation in Left Ventricular-to-Right Atrial Shunt Patients.

Background: The possible association between atrial fibrillation (AF) and left ventricular-to-right atrial shunt (LVRAS) has never been reported yet. The present study investigated the incidence of AF in LVRAS. Methods: This was a retrospective study of consecutive patients undergoing echocardiography at a single tertiary center. Clinical data, laboratory results and echocardiography parameters such as right atrial area (RAA), right ventricular end diastolic diameter (RVDD) and left atrial diameter (LAD) were compared between LVRAS group and non-LVRAS patients, and between AF and non-AF patients. Propensity score matching was performed to decrease the effect of confounders. Logistic regression analysis and mediation analysis were used to estimate the relationship between LVRAS and AF. Results: A total of 3,436 patients were included, and the incidence of LVRAS was 1.16% (n = 40). The LVRAS group had significantly larger RAA, RVDD and LAD compared with non-LVRAS group. Those who suffered from AF showed larger RAA, RVDD and LAD compared with those who maintained sinus rhythm. Multivariable logistic regression showed that gender (OR: 0.608), age (OR: 1.048), LAD (OR: 1.111), mean pulmonary artery blood pressure (mPAP, OR: 1.023), TR (OR: 2.309) and LVRAS (OR: 12.217) were significant factors for AF. RAA could partially mediate the relationship between LVRAS and AF according to the result of mediation analysis. Conclusions: Our study suggested that LVRAS, TR, LAD, mPAP, age and male were risk factors for AF. RA enlargement might underlie mechanism in the higher incidence of AF in LVRAS patients. These findings should be confirmed in larger prospective studies.

PKCß/NF-κB pathway in diabetic atrial remodeling.

Atrial remodeling in diabetes is partially attributed to NF-κB/TGF-ß signal transduction pathway activation. We examined whether the hyperglycemia-induced increased expression of NF-κB/TGF-ß was dependent upon protein kinase C-ß (PKCß) and tested the hypothesis that selective inhibition of PKCß using ruboxistaurin (RBX) can reduce NF-κB/TGF-ß expression and inhibit abnormal atrial remodeling in streptozotocin (STZ)-induced diabetic rats. The effects of PKCß inhibition on NF-κB/TGF-ß signal transduction pathway-mediated atrial remodeling were investigated in STZ-induced diabetic rats. Mouse atrial cardiomyocytes (HL-1 cells) were cultured in low- or high-glucose or mannitol conditions in the presence or absence of small interference RNA that targeted PKCß. PKCß inhibition using ruboxistaurin (RBX, 1 mg/kg/day) decreased the expression of NF-κBp65, p-IκB, P38MARK, TNF-α, TGF-ß, Cav1.2, and NCX proteins and inducibility of atrial fibrillation (AF) in STZ-induced diabetic rats. Exposure of cardiomyocytes to high-glucose condition activated PKCß and increased NF-κB/TGF-ß expression. Suppression of PKCß expression by small interference RNA decreased high-glucose-induced NF-κB and extracellular signal-related kinase activation in HL-1 cells. Pharmacological inhibition of PKCß is an effective method to reduce AF incidence in diabetic rat models by preventing NF-κB/TGF-ß-mediated atrial remodeling.

Selective N-monomethylation of primary anilines with the controllable installation of N-CH2D, N-CHD2, and N-CD3 units.

The selective N-monomethylation of primary anilines was realized by the use of the Me3N-BH3/N,N-dimethylformamide (DMF) system as the methyl source. This method also allows for the controllable introduction of N-CH2D, N-CHD2, and N-CD3 units with high levels of deuterium incorporation using Me3N-BH3/d7-DMF, Me3N-BD3/DMF and Me3N-BD3/d7-DMF systems, respectively.

Regioselective radical α-borylation of α,ß-unsaturated carbonyl compounds for direct synthesis of α-borylcarbonyl molecules.

Organoboron compounds are highly valuable in synthetic chemistry. In particular, α-borylcarbonyl compounds have shown versatile synthetic applications, owing to fruitful chemistries of both the boryl and carbonyl moieties. However, the synthesis of these molecules still remains tedious and time-consuming. Here we report a straightforward and practical route to synthesize α-borylcarbonyl molecules based on a regioselective radical α-borylation of α,ß-unsaturated carbonyl compounds. The reaction features unusual α-regioselectivity and high functional-group compatibility. Further synthetic applications of new α-borylated products were also demonstrated. DFT and kinetic studies implicated that the α-regioselectivity of ß-aryl-α,ß-unsaturated carbonyl compounds was determined by the thermodynamically more favorable radical α-addition step, whereas the formation of α-addition products from ß-alkyl-α,ß-unsaturated carbonyl compounds was driven by an energetically favored hydrogen atom transfer step. Given that α,ß-unsaturated carbonyl compounds can be easily obtained in abundance and variety, this method enjoys great advantages in diverse and economical synthesis of valuable α-borylcarbonyl molecules.

Fabricating and regulating peroxidase-like activity of eggshell membrane-templated gold nanoclusters for colorimetric detection of staphylococcal enterotoxin B.

Fluorescent eggshell membrane-templated gold nanoclusters (Au-ESM) can be obtained in a facile and low-cost manner in this study. The fluorescence of the Au-ESM may be significantly quenched by mercapto-compounds and peroxidase-like activity of Au-ESM could be regulated by the reaction process with glutathione. Moreover, the catalytic activity of the mimetic enzyme membrane could be modulated by immunoreactions. An immunoassay for colorimetric determination of staphylococcal enterotoxins B (SE-B) using colored gold nanoparticles was established based on the catalytic activity adjusted by the target molecules. This colorimetric assay can detect SE-B at the concentration range of 0.4-20 ng/mL and the limit of detection (LOD) is 0.12 ng/mL. As a practical application, the proposed colorimetric assay was further utilized to detect SE-B in food samples such as flour, corn and rice, requiring very low volume of sample and exhibiting great sensitivity and high accuracy, which provides promising platform for development of point-of-care diagnostic devices with biomedical and food safety applications.

Radical Borylative Cyclization of 1,6-Dienes: Synthesis of Boron-Substituted Six-Membered Heterocycles and Carbocycles.

A radical borylative cyclization reaction of 1,6-dienes was developed to assemble boron-handled six-membered heterocycles and carbocycles. This reaction was initiated by the chemo- and regio-controlled addition of an N-heterocyclic carbene-boryl radical to one of the alkene tethers, followed by an intramolecular 6- exo cyclization to afford a six-membered ring framework. The utility of this method was demonstrated in the synthesis of diverse paroxetine analogues through late-stage derivatization of the boryl functional unit.

Radical Borylation/Cyclization Cascade of 1,6-Enynes for the Synthesis of Boron-Handled Hetero- and Carbocycles.

A synthetic method to construct boron-handled cyclic molecules was developed based on a radical borylation/cyclization cascade of 1,6-enynes. The process was initiated by the chemo- and regio-controlled addition of an N-heterocyclic carbene-boryl radical to an alkene or alkyne, followed by ring closure to afford boron-substituted cyclic skeletons. Further molecular transformations of the cyclic products to synthetically useful building blocks were also demonstrated.

Effects of Fuzhuan Brick-Tea Water Extract on Mice Infected with E. coli O157:H7.

Fuzhuan brick-tea extract (FBTE) affects the physiology of mice infected with Escherichia coli O157:H7. For 10 consecutive days, 0.05, 0.5, and 1.0 g/mL FBTE was administered intragastrically to three groups of infected Kunming mice, and changes in immunological function, hematology, and histopathology were examined. The results revealed upregulation of platelets, total protein, and albumin along with downregulation of serum triglycerides, aspartate aminotransferase, creatinine, and urea nitrogen in FBTE-treated mice. Histological sections of stomach, kidney, duodenum, ileum, and colon suggested that infected mucous membranes could be rehabilitated by low- and high-dose FBTE and that inflammation was alleviated. Similarly, increased thymic function in mice treated with middle- and high-dose FBTE led to elevated serum hemolysin antibody titer and increased CD4+ and CD8+ T cells, as indicated by CD4+ and CD8+ expression on intestinal mucosa. Monocyte and macrophage function was improved by three FBTE dosages tested. Colonic microbiota analysis by denaturing gradient gel electrophoresis (DGGE) revealed characteristic bands in infected mice treated with middle- and high-dose FBTE and increased species diversity in Lactobacillus, Bacteroides, and Clostridium cluster IV. These results suggest that FBTE may protect kidney and liver of mice infected with E. coli O157:H7, improve immune function, and regulate the colonic microbiota.

A one-pot synthetic strategy for construction of the dibenzodiazepine skeleton via a transition metal-free process.

A one-pot transition metal-free methodology for constructing pharmacologically active dibenzodiazepine derivatives was developed. Fluoro-, bromo- and nitro-substituted aryl aldehydes were applied to this reaction efficiently.

Fungal community associated with fermentation and storage of Fuzhuan brick-tea.

Chinese Fuzhuan brick-tea is a unique microbial fermented tea characterized by a period of fungal growth during its manufacturing process. The aim of the present study was to characterize, both physicochemically and microbiologically, traditional industrial production processes of Fuzhuan brick-tea. Fermenting tea samples were collected from the largest manufacturer. Physicochemical analyses showed that the low water content in the tea substrates provided optimal growth conditions for xerophilic fungi. The fungal communities existing in tea materials, fermenting tea, and stored teas were monitored by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) targeting the D1 region of the 26S rRNA genes, followed by sequencing of the amplicons. Results revealed that the microorganisms were from, or closely related to, the genera Eurotium, Debaryomyces, Aspergillus, Verticillium, Pichia, Pestalotiopsis, Rhizomucor and Beauveria. This is the first report of Debaryomyces participating in the processing of Fuzhuan brick-tea. We concluded that the dominant genera Eurotium, Debaryomyces and Aspergillus are beneficial fungi associated with the fermentation of Fuzhuan brick-tea. The genus Beauveria was present in the stored Fuzhuan brick-tea, which may help protect tea products from insect spoilage. The remaining four genera were of minor importance in the manufacturing of Fuzhuan brick-tea. The predominant Eurotium species, a strain named Eurotium sp. FZ, was phenotypically and genotypically identified as Eurotium cristatum. High performance thin layer chromatography analysis of anthraquinones showed that emodin existed in all the dark tea samples, but physcion was only detectable in the tea fermented by E. cristatum. The PCR-DGGE approach was an effective and convenient means for profiling the fungal communities in Fuzhuan brick-tea. These results may help promote the use of microbial consortia as starter cultures to stabilize and improve the quality of Fuzhuan brick-tea products.