Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz.

PURPOSE: To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the in vivo and in vitro metabolism of efavirenz. MAIN METHODS: In vitro enzyme systems using rat and human liver microsomes (RLM/HLM) were established, with in vivo studies conducted on Sprague-Dawley rats. Metabolite detection was performed via LC-MS/MS. Human recombinant CYP2B6 microsomes were prepared using a baculovirus-insect cell system and ultracentrifugation, with efavirenz serving as the substrate to study enzyme kinetics. RESULTS: Isavuconazole exhibited an IC50 of 21.14 ± 0.57 µM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC50 of 40.44 ± 4.23 µM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, Tmax, and Cmax of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, Tmax, and Cmax of 8-OH-efavirenz. The activity of CYP2B6.4, 6, and 7 increased significantly compared to CYP2B6.1, with relative clearance ranging from 158.34% to 212.72%. Conversely, the activity of CYP2B6.3, 8, 10, 11, 13-15, 18-21, 23-27, 31-33, and 37 was markedly reduced, ranging from 4.30% to 79.89%. CONCLUSION: Variations in liver enzyme activity and CYP2B6 genetic polymorphisms can significantly alter the metabolism of efavirenz. It provides laboratory-based data for the precise application of efavirenz and other CYP2B6 substrate drugs.

Discovery and Enzyme Kinetic Characterization of Novel CYP2D6 Variants.

Cytochrome P450 2D6 (CYP2D6) exhibits rich genetic polymorphism, and functional changes caused by variations are the key reasons for differences in substrate drug systemic exposure. Discovering novel variants and defining their enzymatic kinetic characteristics can contribute to the personalized application of drugs. In this study, a data chain of variant-function-structure was established through population-based sequencing, baculovirus insect cell expression, in vitro enzymatic incubation, and ultrahigh performance liquid chromatography tandem mass spectrometry. Results revealed nine novel missense mutations in the exonic regions. After the corresponding microsomes were obtained, the kinetics of the variants were investigated using dextromethorphan as a probe substrate. It was found that the activities of CYP2D6.2, 10, 17, 35, 65, R28G, T76M, and E215K were significantly reduced, while D301V almost led to loss of enzyme function. Additionally, the relative clearance rate of R25Q was significantly increased. From the molecular structure perspective, the mutation sites are distributed outside the dextromethorphan binding pocket, suggesting that they primarily influence CYP2D6 activity via allosteric modulation. These research findings provide fundamental data for the precise application of CYP2D6 substrate drugs.

Unlocking the Potential of Collagenases: Structures, Functions, and Emerging Therapeutic Horizons.

Collagenases, a class of enzymes that are specifically responsible for collagen degradation, have garnered substantial attention because of their pivotal roles in tissue repair, remodeling, and medical interventions. This comprehensive review investigates the diversity, structures, and mechanisms of collagenases and highlights their therapeutic potential. First, it provides an overview of the biochemical properties of collagen and highlights its importance in extracellular matrix function. Subsequently, it meticulously analyzes the sources of collagenases and their applications in tissue engineering and food processing. Notably, this review emphasizes the predominant role played by microbial collagenases in commercial settings while discussing their production and screening methods. Furthermore, this study elucidates the methodology employed for determining collagenase activity and underscores the importance of an accurate evaluation for both research purposes and clinical applications. Finally, this review highlights the future research prospects for collagenases, with a particular focus on promoting wound healing and treating scar tissue formation and fibrotic diseases.

Multi-frequency sono-fermentation with mono and co-cultures of LAB synergistically enhance mulberry juice: Evidence from metabolic, micromorphological, sensorial, and computational approaches.

The effect of multi-frequency ultrasound-assisted (20/28/40 KHz) lactic acid bacteria (LAB- Lacticaseibacillus casei, Lactiplantibacillus plantarum, Lacticaseibacillus paracasei, Lactobacillus acidophilus, and Lactobacillus helveticus) fermentation (mono and co-cultures) on the metabolic, structural, micromorphological, and sensorial properties of mulberry juice were evaluated. Results indicated that multi-frequency ultrasound-assisted fermentation significantly modified the microstructure of mulberry juice powder, resulting in more porous and rougher surfaces with irregular indentations. Total phenolic content in the best-performing sample (S10) increased to 365.36 mg GAE/mL, while total flavonoid content rose to 139.20 mg RE/mL (p < 0.05). Antioxidant activity, as measured by DPPH and FRAP assays, also showed considerable improvement, with DPPH scavenging activity increasing to 87.45 % and FRAP-value to 3.27 mM TE/mL (p < 0.05). Additionally, HPLC-UV analysis revealed that the amendment in the concentrations of cyanidin-3-rutinoside (47.47 mg/L) and peonidin-3-O-glucoside (66.86 mg/L) in the S2-based sample. E-nose analysis demonstrated intense flavor profiles in fermented samples, particularly in sample S15. Sensory evaluation also highlighted that the fruity and floral aromas in co-culture fermented samples were enhanced, notably in S10, S7, and S14. Thus, combining multifrequency ultrasonication and fermentation significantly enhances the antioxidants capacity, flavor profile, micro-morphology, and overall quality of mulberry juice.

High-resolution full-coverage ozone (O3) estimates using a data-driven spatial random forest model in Beijing-Tianjin-Hebei region, China.

The Beijing-Tianjin-Hebei (BTH) region is severely polluted by ozone (O3). Accurate O3 estimates are essential for identifying high-polluted zones and developing targeted interventions to relieve the burden of diseases. Although many studies have estimated high-resolution O3 concentrations in BTH, the estimation accuracies are still insufficient. In this study, we incorporated data-driven spatial weight matrices (DDWs) into a random forest (RF) model to fully utilize both the spatial homogeneity and heterogeneity of maximum daily 8-h ozone concentration (MDA8O3), and obtained full-coverage MDA8O3 concentrations at 1 km×1 km in BTH from 2014 to 2022. DDW-RF exhibited satisfactory accuracy (10-fold cross-validation R2 =0.937, RMSE=13.919 µg/m3). Overall O3 level presented a spatial pattern of lower in the north and higher in the southeast and showed a distinct temporal trend, i.e., first increasing and then decreasing during 2014-2021 and increasing slightly in 2022. The accurate MDA8O3 estimates indicates that more attention and resources should be poured into the areas adjacent to Bohai Rim, Shandong and Henan. Regulated operation of factories under specific meteorological conditions and upgrading industrial structure and production modes are recommended to mitigate the formation of O3 precursors and reduce O3 generation. Our findings provide evidence and reference for environmental cleaning policies and targeted interventions.

New drug combination regimen based on pharmacokinetic characteristics-Erdafitinib combined with sertraline or duloxetine.

The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

Machine learning predicts acute respiratory failure in pancreatitis patients: A retrospective study.

PURPOSE: The purpose of the research is to design an algorithm to predict the occurrence of acute respiratory failure (ARF) in patients with acute pancreatitis (AP). METHODS: We collected data on patients with AP in the Medical Information Mart for Intensive Care IV database. The enrolled observations were randomly divided into a 70 % training cohort and a 30 % validation cohort, and the observations in the training cohort were divided into ARF and non-ARF groups. Feature engineering was conducted using random forest (RF) and least absolute shrinkage and selection operator (LASSO) methods in the training cohort. The model building included logistic regression (LR), decision tree (DT), k-nearest neighbours (KNN), naive bayes (NB) and extreme gradient boosting (XGBoost). Parameters for model evaluation include receiver operating characteristic (ROC) curve, precision-recall curve (PRC), calibration curves, positive predictive value (PPV), negative predictive value (NPV), true positive rate (TPR), true negative rate (TNR), accuracy (ACC) and F1 score. RESULTS: Among 4527 patients, 445 patients (9.8 %) experienced ARF. Ca, ALB, GLR, WBC, AG and BUN have been included in the prediction model as features for predicting ARF. The AUC of XGBoost were 0.86 (95 %CI 0.84-0.88) and 0.87 (95 %CI 0.84-0.90) in the training and validation cohorts. In the training cohort, XGBoost demonstrates a true positive rate (TPR) of 0.662, a true negative rate (TNR) of 0.884, a positive predictive value (PPV) of 0.380, a negative predictive value (NPV) of 0.960, an accuracy (ACC) of 0.862, and an F1 score of 0.483. In the validation cohort, XGBoost shows a TPR of 0.620, a TNR of 0.895, a PPV of 0.399, an NPV of 0.955, an ACC of 0.867, and an F1 score of 0.486. CONCLUSION: The XGBOOST model demonstrates good discriminatory ability, which enables clinicians to ascertain the probability of developing ARF in AP patients.

A Novel Synthesis Method of Dumbbell-like (Gd1-xTbx)2O(CO3)2·H2O Phosphor for Latent Fingerprint.

A novel method for synthesizing dumbbell-shaped (Gd1-xTbx)2O(CO3)2·H2O (GOC:xTb3+) phosphors using sodium carbonate was investigated. An amount of 1 mmol of stable fluorescent powder can be widely prepared using 3-11 mmol of Na2CO3 at a pH value of 8.5-10.5 in the reaction solution. The optimal reaction conditions for the phosphors were determined to be 7 mmol for the amount of sodium carbonate and a pH of 9.5 in the solution. Mapping analysis of the elements confirmed uniform distribution of Gd3+ and Tb3+ elements in GOC:xTb3+. The analysis of fluorescence intensity shows that an optimal excitation wavelength of 273 nm is observed when the concentration of Tb3+ is between 0.005 and 0.3. The highest emission intensity was observed for GOC:0.05Tb3+ with a 57.5% maximum quantum efficiency. The chromaticity coordinates show that the color of GOC:Tb3+ is stable and suitable for fluorescence recognition. Latent fingerprint visualization reveals distinctive features like whorls, hooks, and bifurcations. Therefore, the sodium carbonate method offers an effective alternative to traditional urea chemical reaction conditions for preparing GOC:Tb3+.

Decoding sunitinib resistance in ccRCC: Metabolic-reprogramming-induced ABAT and GABAergic system shifts.

Sunitinib, a primary treatment for clear cell renal cell carcinoma (ccRCC), frequently encounters the challenge of resistance development. Metabolic reprogramming, a characteristic change in ccRCC, is likely linked to this resistance. Our research revealed a notable decrease in the expression of the key metabolic gene ABAT in ccRCC, which contributed to diminished sensitivity to sunitinib. Downregulation of ABAT led to an increase in the intracellular level of gamma-aminobutyric acid (GABA), triggering abnormal activation of the G-protein-coupled receptor GABA-B. This activation resulted in increased transactivation of the tyrosine kinase receptors SYK and LYN, thereby reducing the antitumor and antiangiogenic properties of sunitinib. However, the application of SYK and LYN inhibitors successfully inhibited this effect. The transactivation of SYK and LYN caused resistance to the antiangiogenic effects of sunitinib through the upregulation of PGF protein levels. Furthermore, the combined application of an LYN inhibitor with sunitinib has been shown to enhance therapeutic efficacy.

Direct shear behaviors of excavated clay reinforced with geocomposite drainage layer encapsulated in thin sand layers.

The objective of this study is to assess the effectiveness of a novel structure comprising a geocomposite drainage layer and a thin sand layer (GDL + sand) in mitigating the rapid dumping of excavated clay and its associated issues, such as landslides. Two sets of direct shear tests were conducted to investigate the influence of sand layer thickness and compaction degree on the interface shear behavior of the GDL + sand structure. As the sand layer thickness increased, both the interface shear strength and friction angle gradually increased, first more sharply and then at a slower rate toward stability, while the interface cohesion decreased gradually. The optimal sand layer thickness for achieving the most effective reinforcement in stabilizing the clay was identified as 10 mm. A higher sand layer compaction degree was found to result in increased interface shear strength, interface friction angle, and interface cohesion. Building on these findings, the reinforcing efficiency of the GDL + sand structure was investigated through mechanism analysis in comparison to that of a geogrid + sand structure and GDL structure as per the interface friction coefficient. The ranking of interface friction coefficients among the three structures emerged as: geogrid + sand > GDL + sand > GDL. These results suggests that the GDL + sand structure exhibits superior reinforcement efficiency compared to the GDL structure and offers better drainage efficiency than the geogrid + sand structure.

High expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) associated with Diquat-induced damage.

Diquat (DQ) is a commonly used bipyridine herbicide known for its toxic properties and adverse effects on individuals. However, the mechanism underlying DQ-induced damage remain elusive. Our research aimed to uncover the regulatory network involved in DQ-induced damage. We analyzed publicly accessible gene expression patterns and performed research using a DQ-induced damage animal model. The GSE153959 dataset from the Gene Expression Omnibus collection and the animal model of DQ-induced kidney injury were used to identify differentially expressed genes (DEGs). Pathways including the regulation of DNA-templated transcription in response to stress, RNA polymerase II transcription regulator complex and transcription coregulatory activity were shown to be enriched in 21 DEGs. We used least absolute shrinkage and selection operator (LASSO) regression analysis to find possible diagnostic biomarkers for DQ-induced damage. Then, we used an HK-2 cell model to confirm these results. Additionally, we confirmed that 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was the major gene associated with DQ-induced damage using multi-omics screening. The sample validation strongly suggested that HMGCS2 has promise as a diagnostic marker and may provide new targets for therapy in the context of DQ-induced damage.

The impact of CYP3A4 genetic polymorphism on crizotinib metabolism and drug-drug interactions.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.

Effect of superheated steam treatment on enzyme inactivation, morphostructural, physicochemical and digestion properties of sand rice (Agriophyllum squarrosum) flour.

The lipase (LA) and peroxidase (POD) activities, as well as morphological structure, physicochemical and digestion properties of sand rice flour (SRF) treated with superheated steam (SS), were investigated. SS treatment at 165 °C completely deactivated LA and resulted in a 98% deactivation of POD activities in SRF. This treatment also intensified gelatinization, induced noticeable color alterations, and decreased pasting viscosities. Furthermore, there was a moderate reduction in crystal structure, lamellar structure, and short-range ordered structure, with a pronounced reduction at temperatures exceeding 170 °C. These alterations significantly impacted SRF digestibility, leading to increased levels of rapidly digestible starch (RDS) and resistant starch (RS), with the highest RS content achieved at 165 °C. The effectiveness of SS treatment depends on temperature, with 165 °C being able to stabilize SRF with moderate changes in color and structure. These findings will provide a scientific foundation for SS applicated in SRF stabilization and modification.

Genetic variants, haplotype determination, and function of novel alleles of CYP2B6 in a Han Chinese population.

Amino acid variants in protein may result in deleterious effects on enzymatic activity. In this study we investigate the DNA variants on activity of CYP2B6 gene in a Chinese Han population for potential use in precision medicine. All exons in CYP2B6 gene from 1483 Chinese Han adults (Zhejiang province) were sequenced using Sanger sequencing. The effects of nonsynonymous variants on recombinant protein catalytic activity were investigated in vitro with Sf12 system. The haplotype of novel nonsynonymous variants with other single nucleotide variants in the same allele was determined using Nanopore sequencing. Of 38 alleles listed on the Pharmacogene Variation Consortium, we detected 7 previously reported alleles and 18 novel variants, of which 11 nonsynonymous variants showed lower catalytic activity (0.00-0.60) on bupropion compared to CYP2B6*1. Further, these 11 novel star-alleles (CYP2B6*39-49) were assigned by the Pharmacogene Variation Consortium, which may be valuable for pharmacogenetic research and personalized medicine.

Facile superhydrophobic modification on HPMC film using polydimethylsiloxane and starch granule coatings.

The excessive water sensitivity of hydroxypropyl methylcellulose (HPMC) films prevent them from being used extensively. In order to overcome this limitation, superhydrophobic HPMC films were meticulously crafted through the utilization of a composite of polydimethylsiloxane (PDMS) and ball-milled rice starch, corn starch, or potato starch (RS/CS/PS) for the coating process. Initially possessing hydrophilic properties, the HPMC Film (CA = 49.3 ± 1.8°) underwent a transformative hydrophobic conversion upon the application of PDMS, resulting in a static contact angle measuring up to 103.4 ± 2.0°. Notably, the synergistic combination of PDMS-coated HPMC with ball-milled starch demonstrated exceptional superhydrophobic attributes. Particularly, the treated HPMC-based film, specifically the HP-CS-2 h film, showcased an impressive contact angle of 170.5° alongside a minimal sliding angle of 5.2°. The impact of diverse starch types and the ball milling treatment on the PDMS/starch coatings and HPMC film was thoroughly examined using scanning electron microscopy (SEM), wide-angle X-ray diffraction (WAXS), and particle size analysis. These studies demonstrated that the low surface energy and roughness required for the creation of superhydrophobic HPMC-based films were imparted by the hierarchical structure formed by the application of PDMS/ball-milled starch. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Polydimethylsiloxane (PubChem CID: 24764); Hydroxypropyl methylcellulose (PubChem CID: 671); Ethyl acetate (PubChem CID: 8857).

Effect of endogenous protein and lipid removal on the physicochemical and digestion properties of sand rice (Agriophyllum squarrosum) flour.

The study investigated the effect of removing protein and/or lipid on the physicochemical characteristics and digestibility of sand rice flour (SRF). Morphological images showed that protein removal had a greater impact on exposing starch granules, while lipids acted as an adhesive. The treatment altered starch content in SRF samples, leading to increased starch crystallinity, denser semi-crystalline region, lower onset gelatinization temperature (To), higher peak viscosity and gelatinization enthalpy (ΔH), where Protein removal showed a more pronounced effect on altering physicochemical properties compared to lipid removal. The research revealed a positive correlation between rapidly digestible starch (RDS), maximum degree of starch hydrolysis (C∞), digestion rate constant (k) values and 1047/1022 cm-1 ratio, showing a strong connection between short-range structure and starch digestibility. The presence of endogenous proteins and lipids in SRF hinder digestion by restricting starch swelling and gelatinization, and physically obstructing enzyme-starch interaction. Lipids had a greater impact on starch digestibility than proteins, possibly due to their higher efficacy in reducing digestibility, higher lipid content with greater potential to form starch-lipid complexes. This study provides valuable insights into the interaction between starch and proteins/lipids in the sand rice seed matrix, enhancing its applicability in functional and nutritional food products.

Fixed Yellow-to-Blue Intensity Ratio of Dy3+ in KY(CO3)2 Host for Emission Color Tuning.

Dy3+, Ce3+ co-doped KY(CO3)2 phosphors with a monoclinic structure were synthesized using the hydrothermal method to create a fixed yellow-to-blue ratio emission. The [YO8] polyhedron, consisting of a Y atom and eight oxygen atoms, forms a relatively independent microstructure within the KY(CO3)2 host. Y3+ ions are partially replaced by Ce3+ or Dy3+ ions to construct the [CeO8] or [DyO8] polyhedral fluorescence emission unit. The spectral measurements indicate that Ce3+ and Dy3+ can maintain relatively independent fluorescence emission characteristics in the KY(CO3)2 host. The yellow-to-blue intensity ratio of Dy3+ remains close to 1 and does not change with the variation in the doping concentration of KY(CO3)2:Dy3+ and KY(CO3)2:Dy3+,Ce3+ phosphors. When Ce3+ and Dy3+ are co-doped with KY(CO3)2, the emission intensities of Dy3+ under 339 nm and 365 nm excitation increase by 8.43 and 2.32 times, respectively, through resonance energy transfer and cross-relaxation. All Ce3+-doped KY(CO3)2:Dy3+ phosphors can emit white light. Among them, the emitted light of KY(CO3)2:3%Dy3+,5%Ce3+ is closest to standard daylight. Therefore, a stable [YO8] polyhedral structure can be used to achieve more color tuning of light.

LncRNA LBX2-AS1 promotes proliferation and migratory capacity of clear cell renal cell carcinoma through mitophagy.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been extensively investigated in the field of cancer, among which, lncRNA ladybird homeobox 2-antisense RNA 1 (LBX2-AS1) has been demonstrated to exert carcinogenic effects on a variety of malignancies. However, the biological functions of LBX2-AS1 in clear cell renal cell carcinoma (ccRCC) have not been explicitly elucidated. METHODS: Arraystar lncRNA chip and qRT-PCR verify the expression of LncRNA LBX2-AS1 in ccRCC. CCK-8 assay and cell cloning assay were used to assess the proliferative capacity of ccRCC cells. Migration abilities were quantified by scratch assay and transwell assay. Potential molecular signaling pathways were determined by high-throughput whole transcriptomics analysis. WB analysis was performed to validate the relationship between LBX2-AS1 and key molecules of mitophagy pathway. The effect of LBX2-AS1 on mitophagy was observed by laser confocal microscopy. Rescue experiments further validated the role of downstream gene FOXO3A in the LBX2-AS1 signaling pathway. Finally, the authentic effect of LBX2-AS1 was verified in vivo. RESULTS: LncRNA LBX2-AS1 was over expressed in ccRCC tissues and could enhance the proliferation and migration of ccRCC cells. Autophagic pathway was identified as a possible mechanism involved in the oncogenic effect of LBX2-AS1. Mitophagy levels were observed in LBX2-AS1 low-expressing cells through laser confocal microscopy. Knockdown of LBX2-AS1 significantly elevated mitophagy levels as observed using laser confocal microscopy and led to FOXOA3 decreasing in and BNIP3L and LC3 enrichment. Meanwhile, LBX2-AS1 knocking down dampened the proliferation of ccRCC cells in vivo.

Outcomes of structure, function and flavor of pea protein isolate treated by AC, DC and pulsed electric fields.

Based on the standpoint of low carbon footprint processing and less denaturation of plant protein ingredient, the effects of pulsed electric field (PEF), direct current electric field (DCEF), and alternating current electric field (ACEF) treatments on the structure, functional properties and volatile compounds of pea protein isolate were investigated. The results showed that the electric fields (EFs) caused both blueshifts (max. âˆ¼8 cm-1) and redshifts (max. âˆ¼7 cm-1) in the IR spectra and blueshifts (max. âˆ¼5 nm) in the UV spectra. PEF caused an increase of emulsifying activity index and a decrease of emulsion stability index to DCEF and ACEF. A total of 27 volatile compounds were identified and the EFs could cause emerging of new volatiles and disappearing of inherent volatiles potentially to modify the flavor of products. Alterations were significantly observed among the types of EF, but seldomly among the operating parameter levels in the same EF.

The combination of propylene glycol and vegetable glycerin e-cigarette aerosols induces airway inflammation and mucus hyperconcentration.

Despite concerns over their safety, e-cigarettes (e-cigs) remain a popular tobacco product. Although nicotine and flavors found in e-cig liquids (e-liquids) can cause harm in the airways, whether the delivery vehicles propylene glycol (PG) and vegetable glycerin (VG) are innocuous when inhaled remains unclear. Here, we investigated the effects of e-cig aerosols generated from e-liquid containing only PG/VG on airway inflammation and mucociliary function in primary human bronchial epithelial cells (HBEC) and sheep. Primary HBEC were cultured at the air-liquid interface (ALI) and exposed to e-cig aerosols of 50%/50% v/v PG/VG. Ion channel conductance, ciliary beat frequency, and the expression of inflammatory markers, cell type-specific markers, and the major mucins MUC5AC and MUC5B were evaluated after seven days of exposure. Sheep were exposed to e-cig aerosols of PG/VG for five days and mucus concentration and matrix metalloproteinase-9 (MMP-9) activity were measured from airway secretions. Seven-day exposure of HBEC to e-cig aerosols of PG/VG caused a significant reduction in the activities of apical ion channels important for mucus hydration, including the cystic fibrosis transmembrane conductance regulator (CFTR) and large conductance, Ca2+-activated, and voltage-dependent K+ (BK) channels. PG/VG aerosols significantly increased the mRNA expression of the inflammatory markers interleukin-6 (IL6), IL8, and MMP9, as well as MUC5AC. The increase in MUC5AC mRNA expression correlated with increased immunostaining of MUC5AC protein in PG/VG-exposed HBEC. On the other hand, PG/VG aerosols reduced MUC5B expression leading overall to higher MUC5AC/MUC5B ratios in exposed HBEC. Other cell type-specific markers, including forkhead box protein J1 (FOXJ1), keratin 5 (KRT5), and secretoglobin family 1A member 1 (SCGB1A1) mRNAs, as well as overall ciliation, were significantly reduced by PG/VG exposure. Finally, PG/VG aerosols increased MMP-9 activity and caused mucus hyperconcentration in sheep in vivo. E-cig aerosols of PG/VG induce airway inflammation, increase MUC5AC expression, and cause dysfunction of ion channels important for mucus hydration in HBEC in vitro. Furthermore, PG/VG aerosols increase MMP-9 activity and mucus concentration in sheep in vivo. Collectively, these data show that e-cig aerosols containing PG/VG are likely to be harmful in the airways.