Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes

Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 μM and 2.22 μM for CYP1A2 and CYP3A4, respectively. The metabolism of xanthotoxol obeyed the typical monophasic Michaelis-Menten kinetics and Vmax, Km, and CLint values were calculated as 0.55 nmol·min−1·mg−1, 8.46 μM, and 0.06 mL·min−1·mg−1. In addition, the results of molecular docking showed that xanthotoxol was bound to CYP1A2 with hydrophobic and π-π bond and CYP3A4 with hydrogen and hydrophobic bond. We predicted the hepatic clearance (CLh) and the CLh value was 15.91 mL·min−1·kg−1 body weight. These data were significant for the application of xanthotoxol and xanthotoxol-containing herbs

Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population.

One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway

Skinner operant conditioning model and robot bionic self-learning control

Fuzzy Skinner Operant Conditioning Automaton (FSOCA) sastavljen je na temelju Operant Conditioning mehanizma primjenom teorije neizrazitih skupova. Osnovno obilježje automata FSOCA je sljedeće: neizraziti rezultati stanja pomoću Gausove funkcije koriste se kao skupovi neizrazitog stanja; neizrazita pravila preslikavanja (fuzzy mapping rules) kod fuzzy-conditioning-operacije zamjenjuju stohastičke "conditioning-operant" skupove preslikavanja. Stoga se automat FSOCA može koristiti za opisivanje, simuliranje i dizajniranje raznih samo-organizirajućih radnji fuzzy nesigurnog sustava. Automat FSOCA najprije usvaja online algoritam grupiranja (clustering) u svrhu podjele ulaznog prostora (input space) te koristi intenzitet pobude pravila preslikavanja kako bi odlučio treba li generirati novo pravilo preslikavanja da bi broj pravila preslikavanja bio ekonomičan. Dizajnirani FSOCA automat primijenjen je za reguliranje balansiranja gibanja robota s dva kotača. Kako se učenje nastavlja, odabrana vjerojatnoća fuzzy operanta koji optimalno slijedi postepeno će se povećavati, entropijsko djelovanje fuzzy operanta će se postepeno smanjivati pa će se automatski generirati i izbrisati neizrazita pravila preslikavanja. Nakon otprilike sedamnaest krugova obuke, odabrane vjerojatnosti neizrazitog posljedičnog optimalnog operanta postupno teže prema jednoj, entropija djelovanja neizrazitog operanta postupno se smanjuje i broj neizrazitih pravila preslikavanja postaje optimalan. Tako robot postupno uči vještinu balansiranja gibanja.A Fuzzy Skinner Operant Conditioning Automaton (FSOCA) is constructed based on Operant Conditioning Mechanism with Fuzzy Set theory. The main character of FSOCA automaton is: the fuzzed results of state by Gaussian function are used as fuzzy state sets; the fuzzy mapping rules of fuzzy-conditioning-operation replace the stochastic "conditioning-operant" mapping sets. So the FSOCA automaton can be used to describe, simulate and design various self-organization actions of a fuzzy uncertain system. The FSOCA automaton firstly adopts online clustering algorithm to divide the input space and uses the excitation intensity of mapping rule to decide whether a new mapping rule needs to be generated in order to ensure that the number of mapping rules is economical. The designed FSOCA automaton is applied to motion balanced control of two-wheeled robot. With the learning proceeding, the selected probability of the optimal consequent fuzzy operant will gradually increase, the fuzzy operant action entropy will gradually decrease and the fuzzy mapping rules will automatically be generated and deleted. After about seventeen rounds of training, the selected probabilities of fuzzy consequent optimal operant gradually tend to one, the fuzzy operant action entropy gradually tends to minimum and the number of fuzzy mapping rules is optimum. So the robot gradually learns the motion balance skill

Carbon nanoparticles as a multimodal thermoacoustic and photoacoustic contrast agent

We demonstrated the potential of carbon nanoparticles (CNPs) as exogenous contrast agents for both thermoacoustic (TA) tomography (TAT) and photoacoustic (PA) tomography (PAT). In comparison to deionized water, the CNPs provided a four times stronger signal in TAT at 3 GHz. In comparison to blood, The CNPs provided a much stronger signal in PAT over a broad wavelength range of 450-850 nm. Specifically, the maximum signal enhancement in PAT was 9.4 times stronger in the near-infrared window of 635-670 nm. In vivo blood-vessel PA imaging was performed non-invasively on a mouse femoral area. The images, captured after the tail vein injection of CNPs, show a gradual enhancement of the optical absorption in the vessels by up to 230%. The results indicate that CNPs can be potentially used as contrast agents for TAT and PAT to monitor the intravascular or extravascular pathways in clinical applications

The impact of implicit theories on resilience among Chinese nurses: The chain mediating effect of grit and meaning in life

Implicit theories refer to assumptions people hold about different domains, also known as mindsets. There are two implicit theories on the malleability of one’s ability: entity theory and incremental theory. They constrain and regulate people’s understanding and responses to an individual’s behavior, leading to different social cognitive patterns and behavioral responses. Resilience is a positive adaptation in highly stressful situations that represents mechanisms for coping with and transcending difficult experiences, i.e., a person’s ability to successfully adapt to change, resist the adverse effects of stressors, avoid significant dysfunction, and be chronically affected by considered a protective factor for mental health. Although previous studies showed that individuals’ implicit theories are associated with resilience, this relationship has received little attention in the nursing population. It is unclear which variables may contribute to explaining the relationship between implicit theories and resilience. Therefore, the current study aims to deeply explore the relationship between implicit theories and the resilience of Chinese nurses. In addition, we also seek to demonstrate the chain mediating effects of grit and meaning in life on this relationship. We surveyed 709 Chinese nurses through online questionnaires using the self-made demographic questionnaire, the Implicit Theories Scale, the Short Grit Scale, the Meaning in Life Questionnaire, and the 10-item Connor-Davidson Resilience Scale. After controlling for demographic variables such as age, gender, educational background, marital status, professional title, and working years, the results reveal positive associations between Chinese nurses’ implicit theories and their resilience, and grit and meaning in life play a partial mediating role in this relationship, respectively. Furthermore, grit and meaning in life play a chain mediating role between implicit theories and resilience. These findings contribute to understanding the psychological impact mechanism of implicit theories on nurses’ resilience and provide a theoretical basis for nursing managers to formulate strategies to improve nurses’ psychological resilience

The quality of energy- and macronutrient-balanced diets regulates host susceptibility to influenza in mice

Modulation of individual macronutrients or caloric density is known to regulate host resistance to infection in mice. However, the impact of diet composition, independent of macronutrient and energy content, on infection susceptibility is unclear. We show that two laboratory rodent diets, widely used as standard animal feeds and experimental controls, display distinct abilities in supporting mice during influenza infection. Mice placed on the highly processed AIN93G showed increased mortality to infection compared with those on a grain-based chow diet, suggesting a detrimental role for highly processed food in host defense. We further demonstrate that the heightened susceptibility of AIN93G-fed mice was associated with the failure in homeostasis restoration mediated by the cytokine interferon (IFN)-γ. Our findings show that diet composition calibrates host survival threshold by regulating adaptive homeostasis and highlights a pivotal role for extrinsic signals in host phenotype and outcome of host-pathogen interaction

New insights into β-glucan-enhanced immunity in largemouth bass Micropterus salmoides by transcriptome and intestinal microbial composition

β-glucan is widely used in aquaculture due to its immunostimulatory effects, but the specific effect and potential regulatory mechanism on largemouth bass (Micropterus salmoides) are still unclear. Here, we evaluated the effects of β-glucan on growth, resistance to Aeromonas schubertii, intestinal health, and transcriptome of largemouth bass to reveal the potential regulators, metabolic pathways, and altered differential microbiota. Four experimental diets were designed with β-glucan supplementation levels of 0 (control), 100 (LA-100), 200 (MA-200), and 300 (HA-300) mg kg-1, and each diet was fed to largemouth bass (79.30 ± 0.50 g) in triplicate for 70 days, followed by a 3-day challenge experiment. Results showed that different β-glucan supplementations had no significant effects on growth performance and whole-body composition. Fish fed a diet with 300 mg kg-1 β-glucan significantly increased the activity of lysozyme than those fed diets with 0 and 100 mg kg-1 β-glucan. In addition, the survival rate of largemouth bass in β-glucan supplementation groups was significantly higher than the control group at 12- and 24-h challenge by Aeromonas schubertii. Transcriptome analysis showed that a total of 1,245 genes were differentially expressed [|log2(fold change)| ≥1, q-value ≤0.05], including 109 immune-related differentially expressed genes (DEGs). Further analysis revealed that significantly upregulated and downregulated DEGs associated with immunity were mapped into 12 and 24 pathways, respectively. Results of intestinal microflora indicated that fish fed a diet with 300 mg kg-1 β-glucan had higher bacterial richness and diversity as evaluated by Sobs, Chao, Ace, and Simpson indices, but no significant differences were found in the comparison groups. Furthermore, 300 mg kg-1 β-glucan significantly increased the relative abundance of Mycoplasma and decreased Proteobacteria (mainly Escherichia-Shigella and Escherichia coli) and Bacillus anthracis in largemouth bass intestinal microflora. The findings of this study provided new insights that will be valuable in future studies to elucidate the mechanism of immunity enhancement by β-glucan

Disitamab Vedotin (RC48) for HER2-positive advanced breast cancer: a case report and literature review

Background/aimHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with a higher risk of metastasis and poorer overall survival (OS) due to HER2 gene overexpression/amplification. Although anti-HER2 targeted therapy has shown survival benefits in HER2-positive advanced breast cancer (ABC) patients, long-term treatment often leads to drug resistance, complicating further treatment options. RC48, an antibody-drug conjugate (ADC), combines the benefits of antibody targeting with the cytotoxic effects of a small molecule drug.Case reportWe present a case involving a female patient with HER2-positive ABC who developed drug resistance and disease progression following multi-line anti-HER2 targeted therapy. In this instance, RC48 exhibited anti-tumor activity in an ABC patient resistant to HER2-targeted therapy. After eight treatment cycles with 120 mg of RC48, the tumor size decreased and stabilized.ConclusionThis case report underscores the potential clinical value of RC48 as a promising treatment alternative for patients resistant to HER2 targeted therapies