CYP1A1 Gene Research Articles

Impact of Pharmacogenetic Testing on Clozapine Treatment Efficacy in Patients with Treatment-Resistant Schizophrenia.

Managing schizophrenia with clozapine poses a significant challenge due to prevalent therapeutic failures. The increasing interest in personalized medicine underscores the importance of integrating pharmacogenetic information for effective pharmacotherapeutic monitoring in patients. The objective of this study was to explore the correlation between DRD2, HTR2A, SLC6A4, CYP1A2, and ABCB1 polymorphisms and clozapine response in 100 patients with Treatment-Resistant Schizophrenia. Different scales such as the Positive and Negative Syndrome Scale (PANSS), the Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS), the Global Assessment of Functioning Scale (GAF), the Brief Negative Symptom Scale (BNSS), and pharmacokinetic parameters were used to analyse the efficacy of the treatment. Patients who exclusively responded to clozapine compared to the patients with augmentation strategies exhibited distinctive features, such as lower doses, plasma levels, and presented less-pronounced symptomatology. Genetic associations were explored, highlighting SLC6A4, HTR2A, and the *1F/*1F polymorphism for the CYP1A2 gene.

CYP1A2*F Polymorphism Contributes at Least Partially to the Variability of Plasma Levels of Dehydroaripiprazole, an Active Metabolite of Aripiprazole, in Schizophrenic Patients.

The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients. It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported. The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A), and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients. All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis. The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2*C genotype. The absence of the A allele of CYP1A2*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis. The findings of this study suggest that the CYP1A2*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.

Unraveling the Dynamics of Host-Microbiota Indole Metabolism: An Investigation of Indole, Indolin-2-one, Isatin, and 3-Hydroxyindolin-2-one.

The gut microbiota produces a variety of bioactive molecules that facilitate host-microbiota interaction. Indole and its metabolites are focused as possible biomarkers for various diseases. However, data on indole metabolism and individual metabolites remain limited. Hence, we investigated the metabolism and distribution of indole, indolin-2-one, isatin, and 3-hydroxyindolin-2-one. First, we orally administered a high dose of indole into C57BL/6J mice and measured the concentrations of indole metabolites in the brain, liver, plasma, large and small intestines, and cecum at multiple time points using HPLC/MS. Absorption in 30 min and full metabolization in 6 h were established. Furthermore, indole, indolin-2-one, and 3-hydroxiindolin-2-one, but not isatin, were found in the brain. Second, we confirmed these findings by using stable isotope-carrying indole. Third, we identified 3-hydroxyindolin-2-one as an indole metabolite in vivo by utilizing a 3-hydroxyindolin-2-one-converting enzyme, IifA. Further, we confirmed the ability of orally administered 3-hydroxyindolin-2-one to cross the blood-brain barrier in a dose-dependent manner. Finally, we detected upregulation of the CYP1A2 and CYP2A5 genes, confirming the importance of these cytochrome isoforms in indole metabolism in vivo. Overall, our results provide a basic characterization of indole metabolism in the host and highlight 3-hydroxyindolin-2-one as a potentially brain-affecting indole metabolite.

Identification and validation of an individualized metabolic prognostic signature for predicting the biochemical recurrence of prostate cancer based on the immune microenvironment

BackgroundProstate cancer (PCa) is the most prevalent genitourinary malignancy in men, with a significant proportion of patients developing biochemical recurrence (BCR) after treatment. The immune microenvironment and metabolic alterations have crucial implications for the tumorigenesis and progression of PCa. Therefore, identifying metabolic genes associated with the immune microenvironment holds promise for predicting BCR and improving PCa prognosis.MethodsIn this study, ssGSEA and hierarchical clustering analysis were first conducted to evaluate and group PCa samples, followed by the use of the ESTIMATE and CIBERSORT algorithms to characterize the immunophenotypes and tumor microenvironment. The differential metabolic genes (MTGs) between groups were utilized to develop a prognostic-related signature. The predictive performance of the signature was assessed by principal component analysis (PCA), receiver operating characteristic (ROC) curve analysis, survival analysis, and the TIDE algorithm. A miRNA-MTGs regulatory network and predictive nomogram were constructed. Moreover, the expression of prognostic MTGs in PCa was detected by RT‒qPCR.ResultsPCa samples from the TCGA cohort were separated into two groups: the immune-low group and immune-high group. Forty-eight differentially expressed MTGs between the groups were identified, including 37 up-regulated and 11 down-regulated MTGs. Subsequently, CEL, CYP3A4, and PDE6G were identified as the genes most strongly associated with the BCR of PCa patients and these genes were utilized to establish the MTGs-based prognostic signatures. PCA, ROC curves analysis, Kaplan–Meier survival analysis, and the nomogram all showed the good predictive ability of the signature regardless of clinical variables. Furthermore, the MTGs-based signature was indicated as a potential predictive biomarker for immunotherapy response. Nine miRNAs involved in the regulation of prognostic MTGs were determined. In addition to the CEL gene, the PDE6G and CYP3A4 genes were expressed at higher levels in PCa samples.ConclusionsThe MTGs-based signature represents a novel approach with promising potential for predicting BCR in PCa patients.

Dose-dependent exposure to indoxyl sulfate alters AHR signaling, sirtuins gene expression, oxidative DNA damage, and bone mineral status in rats

Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; 100 IS) and high (200 mg/kg b.w.; 200 IS) dose of IS on bone AhR pathway, sirtuins (SIRTs) expression, oxidative DNA damage and bone mineral status in Wistar rats. The accumulation of IS was observed only in trabecular bone tissue in both doses. The differences were observed in the bone parameters, depending on the applied IS dose. The exposure to 100 IS increased AhR repressor (AhRR)-CYP1A2 gene expression, which was associated with SIRT-1, SIRT-3 and SIRT-7 expression. At the low dose group, the oxidative DNA damage marker was unchanged in the bone samples, and it was inversely related to the abovementioned SIRTs expression. In contrast, the exposure to 200 IS reduced the expression of AhRR, CYP1A, SIRT-3 and SIRT-7 genes compared to 100 IS. The level of oxidative DNA damage was higher in trabecular bone in 200 IS group. Femoral bone mineral density was decreased, and inverse relations were noticed between the level of trabecular oxidative DNA damage and parameters of bone mineral status. In conclusion, IS modulates AhR-depending signaling affecting SIRTs expression, oxidative DNA damage and bone mineral status in a dose dependent manner.

Aryl hydrocarbon receptor and IL-13 signaling crosstalk in human keratinocytes and atopic dermatitis.

Atopic dermatitis (AD) is an allergic skin disease mediated by skin barrier impairment and IL-13-driven immune response. Activation of the aryl hydrocarbon receptor (AHR) has shown promise in early clinical trials for AD; however, the mechanism by which AHR partially ameliorates AD is not well known. Gene expression data from human biopsies were analyzed, and compared to gene expression from RNA-sequencing in our in-vitro HaCaT cell model system. Western blot, ELISA qRT-PCR were used to further explore the relationship between AHR and IL-13 signaling in HaCaT cells. The AHR target gene CYP1A1 was decreased in lesional skin compared with healthy control skin (p = 4.30 × 10-9). Single-cell RNA sequencing (scRNAseq) demonstrated increased AHR expression (p < 1.0 × 10-4) and decreased CYP1A1 expression in lesional AD keratinocytes compared with healthy control keratinocytes (p < 0.001). Activation of AHR by AHR agonists in HaCaT cells reversed IL-13-dependent gene expression of several key genes in AD pathogenesis, most notably the eosinophil chemoattractant CCL26 (eotaxin-3). Differentially expressed genes in keratinocytes of patients with AD substantially overlapped with genes regulated by AHR agonists from HaCaT cells by RNAseq, but in reverse direction. Mechanistically, there was evidence for direct transcriptional effects of AHR; AHR binding motifs were identified in the differentially expressed genes from lesional AD keratinocytes compared to control keratinocytes, and AHR activation did not modify IL-13-dependent signal transducer and activator of transcription 6 (STAT6) translocation to the nucleus. Together, these data suggest that the AHR pathway is dysregulated in AD and that AHR modulates IL-13 downstream signaling in keratinocytes through genome-wide, transcriptional regulatory effects.

In vitro study on antioxidant and lipid-lowering activities of tobacco polysaccharides

Tobacco polysaccharides were extracted by hot water extraction, and purified and separated using DEAE-52 cellulose chromatography columns, and three purified polysaccharide fractions, YCT-1, YCT-2, and YCT-3, were finally obtained. The physicochemical properties of the three fractions were analyzed by ultraviolet spectroscopy, high-performance liquid chromatography and high-performance gel chromatography. The in vitro antioxidant activity of tobacco polysaccharides was compared among different fractions by using DPPH radical, hydroxyl radical scavenging assay and potassium ferricyanide method. The in vitro hypoglycemic activity was compared using α-amylase and α-glucosidase activity inhibition assay. And the in vitro hypolipidemic activity were investigated by using pancreatic lipase activity inhibition assay and HepG-2 intracellular lipid accumulation assay. All the results showed that the constituent monosaccharides of the three tobacco polysaccharide fractions were similar, but the molar percentages of each monosaccharide were different. The average molecular weights of the three components were 27,727 Da, 27,587 Da, and 66,517 Da, respectively, and the scavenging activities on DPPH radicals and hydroxyl radicals were at a high level with good quantitative-effect relationships. The reducing power were much lower than that of the positive control VC, and the three polysaccharide fractions had a weak inhibitory ability on α-amylase activity, but showed excellent inhibitory ability on α-glucosidase and pancreatic lipase activity. In addition, the results of cellular experiments showed that all three fractions were able to inhibit lipid over-accumulation in HepG-2 cells by increasing the mRNA expression levels of PPAR-α, CPT-1A, and CYP7A1 genes, and the tobacco polysaccharide YCT-3 showed the best effect. The mechanism by which YCT-3 ameliorated the over-accumulation of intracellular lipids in HepG-2 cells was found to be related to its influence on the expression of miR-155-3p and miR-17-3p in the exosomes of HepG-2 cells.Graphical

The pharmacogenetics of tacrolimus in renal transplant patients: association with tremors, new-onset diabetes and other clinical events.

Our study is the first study to investigate the effect of SNPs in CYP3A5, CYP3A4, ABCB1 and POR genes on the incidence of tremors, nephrotoxicity, and diabetes mellitus. A total of 223 renal transplant patients receiving tacrolimus and mycophenolate mofetil (MMF) were recruited. Both adults and children patients participated in the study. Genotyping was performed using PROFLEX-PCR followed by RFLP. MPA and tacrolimus plasma concentrations were measured by immunoassay. The AUC0-12h of MMF was estimated by a Bayesian method. We found a statistically significant association between the CYP3A5*3 and CYP3A4*1B genotypes and the tacrolimus exposure. We found a lower occurrence of nephrotoxicity (p = 0.03), tremor (p = 0.01), and new-onset diabetes (p = 0.002) associated with CYP3A5*1 allele. The CYP3A4*1B allele was significantly associated with a lower occurrence of new-onset diabetes (p = 0.026). The CYP3A5*1 allele was significantly associated with an increased risk of acute and chronic rejection (p = 0.03 and p < 0.001, respectively). Our results support the usefulness of tacrolimus pharmacokinetics in pre-kidney transplant assessments.

Nitrophenols disrupt the expression and activity of biotransformation enzymes (CYP3A and COMT) in chicken ovarian follicles in vivo and in vitro.

Nitrophenols are environmental pollutants and xenobiotics, the main sources of which are diesel exhaust fumes and pesticides. The biotransformation processes that take place in the liver are defence mechanisms against xenobiotics, such as nitrophenols. Our previous study showed that the chicken ovary is an additional xenobiotic detoxification place and that nitrophenols disrupt steroidogenesis in chicken ovarian follicles. Therefore, the present study aimed to determine the in vivo and in vitro effects of 4-nitrophenol (PNP) and 3-methyl-4-nitrophenol (PNMC) on the expression and activity of phase I (CYP3A) and phase II (COMT) biotransformation enzymes in chicken ovary. In an in vivo study, hens were treated with a vehicle or 10mg PNP or PNMC/kg b.wt. per day for 6 days. In an in vitro study, prehierarchical white and yellowish follicles, as well as the granulosa and theca layers of the three largest preovulatory follicles (F3, F2 and F1), were isolated and then incubated in a control medium or medium supplemented with PNP (10-6M) or PNMC (10-6M) for 24 or 48 h. Both in vivo and in vitro studies showed that nitrophenols exert tissue- and compound-dependent (PNP or PNMC) effects on CYP3A and COMT gene (real-time PCR) protein (Western blot) expression and their activity (colorimetric methods). The inhibitory effect of nitrophenols in vivo on the activity of biotransformation enzymes suggest that the ovary has the capacity to metabolise PNP and PNMC.

Pyrene and its derivatives increase lung adverse effects by activating aryl hydrocarbon receptor transcription

Derivatives of polycyclic aromatic hydrocarbons (PAHs) pose significant threat to environment and human health due to their widespread and potential hazards. However, adverse effects and action mechanisms of PAH derivatives on human health have not been attempted yet. Herein, we chose pyrene and its derivatives (1-hydroxypyrene, 1-nitropyrene, and 1-methylpyrene) to investigate adverse effect mechanism to human lungs using in vitro and in vivo methods. Results showed that pyrene derivatives have higher lung health risks than original pyrene. They can activate AhR, subsequently affecting expression of downstream target genes CYP1A1 and CYP1B1. The binding energies of pyrene and its derivatives ranged from −16.07 to −27.25 kcal/mol by molecular dynamics simulations, implying that pyrene and its derivatives acted as agonists of AhR and increased adverse effects on lungs. Specifically, 1-nitropyrene exhibited stabler binding conformation and stronger AhR expression. In addition, sensitivity of pyrene and its derivatives to AhR activation was attributed to type and number of key amino acids in AhR, that is, pyrene (Leu293), 1-nitropyrene (Cys333, Met348, and Val381), 1-hydroxypyrene (Leu293 and Phe287), and 1-methylpyrene (Met348). In summary, we provide a universal approach for understanding action mechanisms of PAH derivatives on human health, and their adverse effects should be taken seriously.

Investigation of Campylobacter concisus gastric epithelial pathogenicity using AGS cells.

Campylobacter concisus is an oral bacterium. Recent studies suggest that C. concisus may be involved in human gastric diseases. The mechanisms, however, by which C. concisus causes human gastric diseases have not been investigated. Here we examined the gastric epithelial pathogenicity of C. concisus using a cell culture model. Six C. concisus strains and the human gastric epithelial cell line AGS cells were used. IL-8 produced by AGS cells after incubation with C. concisus was measured using enzyme-linked immunosorbent assay (ELISA), and AGS cell apoptosis was determined by caspase 3/7 activities. The effects of C. concisus on actin arrangement in AGS cells was determined using fluorescence staining. The effects of C. concisus on global gene expression in AGS cells was determined by transcriptomic analysis and quantitative real-time PCR (qRT-PCR). The role of the upregulated CYP1A1 gene in gastric cancer survival was assessed using the Kaplan-Meier method. C. concisus induced production of IL-8 by AGS cells with strain variation. Significantly increased caspase 3/7 activities were observed in AGS cells incubated with C. concisus strains when compared to AGS cells without bacteria. C. concisus induced actin re-arrangement in AGS cells. C. concisus upregulated 30 genes in AGS cells and the upregulation of CYP1A1 gene was confirmed by qRT-PCR. The Kaplan-Meier analysis showed that upregulation of CYP1A1 gene is associated with worse survival in gastric cancer patients. Our findings suggest that C. concisus may play a role in gastric inflammation and the progression of gastric cancer. Further investigation in clinical studies is warranted.

Unraveling the link between plasma caffeine concentrations and inflammatory bowel disease risk through Mendelian randomization

BackgroundCaffeine is believed to possess anti-inflammatory properties, yet direct population-based evidence regarding its impact on inflammatory bowel disease (IBD) remains scarce. ObjectivesIn this study, we used 2-sample Mendelian randomization (MR) study to investigate the causal relationship between long-term plasma caffeine concentrations and IBD and its subtypes, ulcerative colitis (UC) and Crohn disease (CD). MethodsWe used single nucleotide polymorphisms (SNPs) associated with plasma caffeine concentrations at genome-wide significance within a ±100-kb range around the CYP1A2 or AHR genes as instrumental variables. Genome-wide association study (GWAS) data for IBD and its subtypes were obtained from FinnGen and International Inflammatory Bowel Disease Genetics Consortium. We conducted a meta-analysis of MR-related SNPs from both sources and used a multiplicative inverse variance–weighted random effects model to combine the effects of each SNP proxy on exposure to outcomes. ResultsIn our study, genetically predicted higher plasma caffeine concentrations were associated with a lower risk of IBD, with an odds ratio (OR) of 0.78 (95% confidence interval [CI]: 0.66, 0.91; PFDR = 0.004). This trend was also observed in UC and CD, with ORs of 0.79 (95% CI: 0.66, 0.94; PFDR = 0.014) and 0.78 (95% CI: 0.62, 0.98; PFDR = 0.032), respectively. ConclusionOur study indicates a potential causal link between genetically predicted higher plasma caffeine concentrations and a reduced risk of IBD, including its subtypes UC and CD.

Betaine supplementation alleviates corticosterone-induced hepatic cholesterol accumulation through epigenetic modulation of HMGCR and CYP7A1 genes in laying hens

Excessive corticosterone (CORT) exposure could cause hepatic cholesterol accumulation in chickens and maternal betaine supplementation could decrease hepatic cholesterol deposition through epigenetic modifications in offspring chickens. Nevertheless, it remains uncertain whether providing betaine to laying hens could protect CORT-induced hepatic cholesterol accumulation via epigenetic mechanisms. This study aimed to examine the effects of dietary betaine on plasma and hepatic cholesterol contents, expression of cholesterol metabolic genes, as well as DNA methylation on their promoters in the liver of laying hens exposed to CORT. A total of 72 laying hens at 130 d of age were randomly divided into 3 groups: control (CON), CORT, and CORT+betaine (CORT+BET) groups. The experiment lasted for 35 d. Chickens in CON and CORT groups were fed a basal diet, whereas the CORT+BET group chickens were fed the basal diet supplemented with 0.1% betaine for 35 d. On d 28 of the experiment, chickens in CORT and CORT+BET groups received daily subcutaneous injections of CORT (4.0 mg/kg body weight), whereas the CON group chickens were injected with an equal volume of solvent for 7 d. The results showed that CORT administration led to a significant increase (P < 0.05) in the contents of cholesterol in plasma and liver, associated with activation (P < 0.05) of sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), lecithin-cholesterol acyltransferase (LCAT) and low-density lipoprotein receptor (LDLR) genes expression, and inhibition of cholesterol-7-alpha hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) genes expression in the liver compared to the CON. In contrast, CORT-induced up-regulation of HMGCR mRNA and protein abundances and downregulation of CYP7A1 mRNA and protein abundances were completely normalized (P < 0.05) by betaine supplementation. Besides, CORT injection led to significant hypomethylation (P < 0.05) on HMGCR promoter and hypermethylation (P < 0.05) on CYP7A1 promoter. Moreover, dietary betaine rescued (P < 0.05) CORT-induced changes in methylation status of HMGCR and CYP7A1 genes promoters. These results indicate that dietary betaine addition protects laying hens from CORT-induced hepatic cholesterol accumulation via epigenetic modulation of HMGCR and CYP7A1 genes.

Signatures of Co-evolution and Co-regulation in the CYP3A and CYP4F Genes in Humans.

Cytochromes P450 (CYP450) are hemoproteins generally involved in the detoxification of the body of xenobiotic molecules. They participate in the metabolism of many drugs and genetic polymorphisms in humans have been found to impact drug responses and metabolic functions. In this study, we investigate the genetic diversity of CYP450 genes. We found that two clusters, CYP3A and CYP4F, are notably differentiated across human populations with evidence for selective pressures acting on both clusters: we found signals of recent positive selection in CYP3A and CYP4F genes and signals of balancing selection in CYP4F genes. Furthermore, an extensive amount of unusual linkage disequilibrium is detected in this latter cluster, indicating co-evolution signatures among CYP4F genes. Several of the selective signals uncovered co-localize with expression quantitative trait loci (eQTL), which could suggest epistasis acting on co-regulation in these gene families. In particular, we detected a potential co-regulation event between CYP3A5 and CYP3A43, a gene whose function remains poorly characterized. We further identified a causal relationship between CYP3A5 expression and reticulocyte count through Mendelian randomization analyses, potentially involving a regulatory region displaying a selective signal specific to African populations. Our findings linking natural selection and gene expression in CYP3A and CYP4F subfamilies are of importance in understanding population differences in metabolism of nutrients and drugs.

Can Skin Aging be Reversible by Anti-Aging Treatments with Genetic Analysis?

Skin aging is affected by internal and external factors. The stratum corneum consists of keratinocytes, and as these mature in the epidermis, their proliferative potential gradually decreases and the skin undergoes programmed destruction. There are many single nucleotid polymorphism (SNP)s associated with skin aging. The COL1A1, MMP1, and CYP1A2 genes are responsible for collagen degradation and production. Changes in these genes affect collagen degradation and production. The MCR1 and STXBP5L genes are important for ultraviolet (UV) protection and moisturizing the skin. Due to changes in these genes, the skin cannot be well protected from UV rays, and skin aging accelerates. As free radicals in the skin increase, oxidative stress increases. The SOD2, GPX1, and GSTP1 genes play a role in protecting the body against oxidative stress. Also, coenzyme Q10 acts against oxidative stress. The change in the NQO1 gene cannot convert coenzyme Q10 to its active form, ubiquinol, which causes increased oxidative stress in the skin. Another factor that affects the aging of the skin is the aggressive immune system. The TNF-α gene influences the inflammatory responses generated by the immune system. If the TNF-α gene is not working properly, it can create an overly aggressive reaction and damage tissue. In addition, vitamin E is a powerful antioxidant, and changes in the APOA5 gene cause vitamin E deficiency. This affects the protection of the skin from UV rays. Another important vitamin for the skin is vitamin C, and the SLC23A1 gene is involved in vitamin C transport. Changes in this gene cause vitamin C deficiency and affect oxidative stress and collagen production in the skin. These polymorphisms affect the intrinsic and extrinsic factors that affect the aging of the skin. In order for individuals to prevent skin aging, these polymorphisms should be analyzed, and skin aging can be delayed with skin care products suitable for the person.

Gelatin-Based Hybrid Hydrogels as Matrices for Organoid Culture.

The application of liver organoids is very promising in the field of liver tissue engineering; however, it is still facing some limitations. One of the current major limitations is the matrix in which they are cultured. The mainly undefined and murine-originated tumor matrices derived from Engelbreth-Holm-Swarm (EHS) sarcoma, such as Matrigel, are still the standard culturing matrices for expansion and differentiation of organoids toward hepatocyte-like cells, which will obstruct its future clinical application potential. In this study, we exploited the use of newly developed highly defined hydrogels as potential matrices for the culture of liver organoids and compared them to Matrigel and two hydrogels that were already researched in the field of organoid research [i.e., polyisocyanopeptides, enriched with laminin-entactin complex (PIC-LEC) and gelatin methacryloyl (GelMA)]. The newly developed hydrogels are materials that have a physicochemical resemblance with native liver tissue. Norbornene-modified dextran cross-linked with thiolated gelatin (DexNB-GelSH) has a swelling ratio and macro- and microscale properties that highly mimic liver tissue. Norbornene-modified chondroitin sulfate cross-linked with thiolated gelatin (CSNB-GelSH) contains chondroitin sulfate, which is a glycosaminoglycan (GAG) that is present in the liver ECM. Furthermore, CSNB-GelSH hydrogels with different mechanical properties were evaluated. Bipotent intrahepatic cholangiocyte organoids (ICOs) were applied in this work and encapsulated in these materials. This research revealed that the newly developed materials outperformed Matrigel, PIC-LEC, and GelMA in the differentiation of ICOs toward hepatocyte-like cells. Furthermore, some trends indicate that an interplay of both the chemical composition and the mechanical properties has an influence on the relative expression of certain hepatocyte markers. Both DexNB-GelSH and CSNB-GelSH showed promising results for the expansion and differentiation of intrahepatic cholangiocyte organoids. The stiffest CSNB-GelSH hydrogel even significantly outperformed Matrigel based on ALB, BSEP, and CYP3A4 gene expression, being three important hepatocyte markers.

Effects of copper nanoparticles on oxidative stress genes and their enzyme activities in common carp (Cyprinus carpio)

Copper nanoparticles (Cu-NPs) are becoming increasingly prevalent in the environment due to their wide range of applications, posing potential threats to living organisms. Negative effects of Cu-NP exposure have been confirmed in many fish species, and they include disorders in the expression of oxidative stress genes and the activity of enzymes they encode. Common carp, known for its sensitivity to nanopollutants in water, serves as a valuable model organism for nanoparticle toxicity assessment. This study investigated the effects of specific Cu-NPs – copper nanopowder (Cu-NPs), colloidal copper nanoparticles (Cu), and copper oxide nanoparticles (CuO-NPs) – on gene expression and enzyme activity (GPX, CYP1A, HSP70, SOD, CAT) in C. carpio hatchlings, utilizing molecular biology tools and biochemical analyses. Results showed that Cu increased the expression of the hsp70 gene, Cu-NPs elevated the expression of the cyp1a and hsp70 genes, and CuO increased cyp1a expression. Conversely, sod and cat exhibited reduced expression across all samples (Cu, Cu-NPs, CuO). All Cu forms induced significant ROS accumulation and notable alterations in oxidative stress biomarkers (SOD, CAT, GPX).

Interaction between CYP1A1 gene polymorphism and environment factors on risk of endometrial cancer.

The purpose of this study was to investigate the impact of single nucleotide polymorphisms (SNPs) of the CYP1A1 gene and the gene-environment interaction on the susceptibility to endometrial cancer in Chinese women. Logistic regression was performed to investigate the association between the four SNPs of the CYP1A1 gene and the risk of endometrial cancer. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the gene-environmental interaction. A total of 934 women with a mean age of 61.7 ± 10.5 years were selected, including 310 endometrial cancer patients and 624 normal controls. The frequency of rs4646421- T allele was higher in endometrial cancer patients than normal controls, the T allele of rs4646421 was 28.1% in endometrial cancer patients and 21.0% in normal controls (p < 0.001). Logistic regression analysis showed that the rs4646421 - T allele was associated with increased risk of endometrial cancer, OR (95% CI) were 1.52 (1.11-1.97) and 1.91 (1.35-2.52), respectively. GMDR analysis found a significant two-locus model (p = 0.0107) involving rs4646421 and abdominal obesity (defined by waist circumference), indicating a potential gene-environment interaction between rs4646421 and abdominal obesity. Abdominal obese subjects with rs4646421- CT or TT genotype have the highest risk of endometrial cancer, compared to non-abdominal obese subjects with the rs4646421- CC genotype, the OR (95%CI) was 2.23 (1.62-2.91). Both the rs4646421- T allele and the interaction between rs4646421 and abdominal obesity were associated with increased risk of endometrial cancer.

Association between CYP3A5 Gene Polymorphism and Post-Transplant Acute Immune Rejection in Renal Transplant Recipients Receiving Tacrolimus Therapy: A Correlation Study.

Acute immune rejection remains a challenge in the post-transplant period, with approximately 7.8% of renal transplant recipients experiencing rejection episodes within the first year. Genetic polymorphisms in the CYP3A5 gene, which influences tacrolimus metabolism, have garnered interest regarding their association with clinical outcomes in renal transplantation. This retrospective correlation study analysed clinical data from kidney transplant patients who received tacrolimus treatment at our hospital from June 2015 to June 2023. The presence of CYP3A5 gene polymorphisms, tacrolimus trough levels, and demographic and clinical data were collected and analysed. A total of 105 kidney transplant patients were included. Patients were divided into acute immune rejection (n = 56) and non-acute immune rejection (n = 49) groups. The distribution of CYP3A5 gene polymorphisms differed significantly between the acute rejection and non-acute rejection groups (p = 0.037). The acute rejection group exhibited a higher frequency of CYP3A5 *1/*1 or *1/*3 genotypes than the non-acute rejection group. No statistically significant differences were found in the tacrolimus trough levels between the two groups. Correlation analysis revealed a statistically significant correlation between CYP3A5 gene polymorphism and post-transplant acute immune rejection (r = 0.223, p < 0.05). This study demonstrated a significant association between CYP3A5 gene polymorphism and the risk of post-transplant acute immune rejection in renal transplant recipients receiving tacrolimus therapy. These findings highlighted the importance of genetic variability in tacrolimus metabolism when managing immunosuppressive therapy in transplant recipients.

Exploring Acute Liver Damage: Slimming Health Foods and CYP3A4 Induction.

Patients taking multiple drugs and various health foods often develop acute hepatitis. We hypothesized that the interaction between health foods and drug metabolism was the cause of severe liver injury in these patients. Therefore, we studied changes in the activity of the drug-metabolizing enzyme, cytochrome P450 (CYP), using slimming health food extracts and elucidated the molecular mechanism of liver injury onset through hepatotoxicity evaluation. For cytotoxicity testing, health food extract samples were added to HepG2 cells derived from hepatic parenchymal cells and culture medium, and cell viability was calculated 48 h after culture. To evaluate CYP3A4 induction, 3-1-10 cells constructed with a reporter linked to CYP3A4 gene were used, and reporter activity was measured 48 h after culture. In the chronological order of the slimming health food intake history of the patient, niacinamide and Gymnema sylvestre extracts strongly inhibited HepG2 cell viability. In contrast, dietary supplements A and Coleus forskohlii extract strongly induced CYP3A4 reporter activity. Coleus forskohlii extract showed the strongest transcriptional activation of CYP3A4 gene. In a mouse model of human-type drug metabolism, forskolin induced CYP3A4 transcription. Thus, we concluded that CYP3A4 induction by Coleus forskohlii is one of the causes of crucial hepatocellular injury, which is a type of liver injury caused by the active metabolite of acetaminophen produced by CYP3A4.