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.

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.

RRGA-Net: Robust Point Cloud Registration Based on Graph Convolutional Attention.

The problem of registering point clouds in scenarios with low overlap is explored in this study. Previous methodologies depended on having a sufficient number of repeatable keypoints to extract correspondences, making them less effective in partially overlapping environments. In this paper, a novel learning network is proposed to optimize correspondences in sparse keypoints. Firstly, a multi-layer channel sampling mechanism is suggested to enhance the information in point clouds, and keypoints were filtered and fused at multi-layer resolutions to form patches through feature weight filtering. Moreover, a template matching module is devised, comprising a self-attention mapping convolutional neural network and a cross-attention network. This module aims to match contextual features and refine the correspondence in overlapping areas of patches, ultimately enhancing correspondence accuracy. Experimental results demonstrate the robustness of our model across various datasets, including ModelNet40, 3DMatch, 3DLoMatch, and KITTI. Notably, our method excels in low-overlap scenarios, showcasing superior performance.

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.

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.

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.

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.

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.

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.

Human-influenced changes in pollution status and potential risk of sediment heavy metals in Xincun Bay, a typical lagoon of Hainan, China.

Pollution status and ecological risks associated with sediment heavy metals (Cu, Pb, Zn, Cd, and Cr) were investigated around Xincun Bay, assessing their spatial variations and relationship with sediment physiochemical factors. Higher concentrations and associated risks were observed in the central region, where mariculture activities were concentrated, compared to non-maricultured areas. Despite with overall low concentrations, Cd had a higher ecological risk. Correlation and principal component analyses revealed similar sources for all metals in Xincun Bay. Heavy metal concentrations varied with expansion of mariculture operations in terms of quantity and scale, confirming the influence of mariculture activities. Sediments around mariculture had higher contents of clay, silt, and total organic carbon (TOC), and finer particle sizes. Quantitative analyses through correlation and linear regression indicated that TOC significantly regulated heavy metal concentration and distribution (p < 0.05). Considering its significant association with TOC, the influence of mean grain size should not be overlooked.

Enhanced interfacial boiling of impacting droplets upon vibratory surfaces.

HYPOTHESIS: Despite the flourishing studies of droplet interfacial boiling, the boiling upon vibratory surfaces, which may cause vigorous liquid-vapor-solid interactions, has rarely been investigated. Enhanced boiling normally can be gained from rapid removal of vapor and disturbance of liquid-vapor interface. We hypothesize that the vibratory surfaces enhance both effects with new intriguing phenomena and thus, attain an enhanced boiling heat transfer. EXPERIMENTS: We experimentally investigated the impacting fluid dynamics and coupled heat transfer patterns of multiple droplets and a single droplet impinging on still and vibratory surfaces of various materials and different wettability. FINDINGS: The boiling under vibratory surfaces with increased vibration velocity amplitude and enhanced wettability can be enhanced by 80% in heat transfer coefficient and Nusselt number, which is attributed to several reasons: shortened bubble lifespan, thinner and smaller bubbles, and enhanced disturbances in liquid-vapor interfaces. The vibration also delays the Leidenfrost point when the droplet impacts a descending surface, which shows that the droplet impact moment (vibration phase angle) is particularly crucial. The descending surface releases the generated vapor actively and facilitates liquid-solid contact, thereby delaying the Leidenfrost. From fundamentals to application, this article strengthens our understanding of vibrated interfacial boiling in scenarios closer to multiple natural processes and practical industries.

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.

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.

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.

Novel Preoperative Type IV Collagen to Predict the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Related Cirrhotic Portal Hypertension After Laparoscopic Splenectomy and Azygoportal Disconnection.

Purpose: Although laparoscopic splenectomy and azygoportal disconnection (LSD) can significantly decrease portal vein pressure and even the incidence of hepatocellular carcinoma (HCC) in patients with cirrhotic portal hypertension (CPH), postoperative HCC inevitably occurs in certain patients. The purpose of this study was to seek a novel preoperative non-invasive predictive indicator to predict the occurrence of postoperative HCC. Patients and Methods: From April 2012 to April 2022, we collected clinical data of 178 hepatitis B virus (HBV)-related CPH patients. Based on inverse treatment probability weighting, candidate variables for predicting postoperative HCC were determined by means analysis. Then, a novel preoperative non-invasive prediction indicator (ie, type IV collagen-alpha fetoprotein-fibrosis-4 score [IVAF-FIB-4]) was established based on candidate variables, and its predictive ability was explored. Results: Postoperative HCC occurred in 9 (5.1%) patients. Correlation analyses showed that the IVAF-FIB-4 had a significant positive correlation with HCC (r = 0.835, P < 0.001). IVAF-FIB-4 showed a high accuracy (the area under the receiver operating characteristic curve: 0.939, 95% confidence interval [CI]: 0.818-1.000; sensitivity: 88.9%; specificity: 93.5%). At the end of follow-up, the incidence density of HCC in patients with IVAF-FIB-4 (1) was significant higher than that in patients with IVAF-FIB-4 (0) (138.1/1000 vs 1.1/1000 person-years; rate ratio: 130.475, 95% CI: 16.318-1043.227). In logistic regression, IVAF-FIB-4 was an independent risk factor for HCC (odds ratio: 668.000, 95% CI: 53.895-8279.541; P < 0.001). Conclusion: IVAF-FIB-4 is a novel preoperative noninvasive predictive indicator for predicting postoperative HCC in HBV-related CPH patients after LSD, with satisfactory predictive ability.