Role of transcriptional cofactors in cardiovascular diseases.

Cardiovascular disease is a main cause of mortality in the world and the highest incidence of all diseases. However, the mechanism of the pathogenesis of cardiovascular disease is still unclear, and we need to continue to explore its mechanism of action. The occurrence and development of cardiovascular disease is significantly associated with genetic abnormalities, and gene expression is affected by transcriptional regulation. In this complex process, the protein-protein interaction promotes the RNA polymerase II to the initiation site. And in this process of transcriptional regulation, transcriptional cofactors are responsible for passing cues from enhancers to promoters and promoting the binding of RNA polymerases to promoters, so transcription cofactors playing a key role in gene expression regulation. There is growing evidence that transcriptional cofactors play a critical role in cardiovascular disease. Transcriptional cofactors can promote or inhibit transcription by affecting the function of transcription factors. It can affect the initiation and elongation process of transcription by forming complexes with transcription factors, which are important for the stabilization of DNA rings. It can also act as a protein that interacts with other proteins to affect the expression of other genes. Therefore, the aim of this overview is to summarize the effect of some transcriptional cofactors such as BRD4, EP300, MED1, EZH2, YAP, SIRT6 in cardiovascular disease and to provide a promising therapeutic strategy for the treatment of cardiovascular disease.

Cervical Spondylosis Diagnosis Based on Convolutional Neural Network with X-ray Images.

The increase in Cervical Spondylosis cases and the expansion of the affected demographic to younger patients have escalated the demand for X-ray screening. Challenges include variability in imaging technology, differences in equipment specifications, and the diverse experience levels of clinicians, which collectively hinder diagnostic accuracy. In response, a deep learning approach utilizing a ResNet-34 convolutional neural network has been developed. This model, trained on a comprehensive dataset of 1235 cervical spine X-ray images representing a wide range of projection angles, aims to mitigate these issues by providing a robust tool for diagnosis. Validation of the model was performed on an independent set of 136 X-ray images, also varied in projection angles, to ensure its efficacy across diverse clinical scenarios. The model achieved a classification accuracy of 89.7%, significantly outperforming the traditional manual diagnostic approach, which has an accuracy of 68.3%. This advancement demonstrates the viability of deep learning models to not only complement but enhance the diagnostic capabilities of clinicians in identifying Cervical Spondylosis, offering a promising avenue for improving diagnostic accuracy and efficiency in clinical settings.

The HNF1α-Regulated LncRNA HNF1α-AS1 Is Involved in the Regulation of Cytochrome P450 Expression in Human Liver Tissues and Huh7 Cells.

Expression of cytochrome P450s (P450s) is regulated by epigenetic factors, such as DNA methylation, histone modifications, and noncoding RNAs through different mechanisms. Among these factors, long noncoding RNAs (lncRNAs) have been shown to play important roles in the regulation of gene expression; however, little is known about the effects of lncRNAs on the regulation of P450 expression. The aim of this study was to explore the role of lncRNAs in the regulation of P450 expression by using human liver tissues and hepatoma Huh7 cells. Through lncRNA microarray analysis and quantitative polymerase chain reaction in human liver tissues, we found that the lncRNA hepatocyte nuclear factor 1 alpha antisense 1 (HNF1α-AS1), an antisense RNA of HNF1α, is positively correlated with the mRNA expression of CYP2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 as well as pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Gain- and loss-of-function studies in Huh7 cells transfected with small interfering RNAs or overexpression plasmids showed that HNF1α not only regulated the expression of HNF1α-AS1 and P450s, but also regulated the expression of CAR, PXR, and aryl hydrocarbon receptor (AhR). In turn, HNF1α-AS1 regulated the expression of PXR and most P450s without affecting the expression of HNF1α, AhR, and CAR. Moreover, the rifampicin-induced expression of P450s was also affected by HNF1α and HNF1α-AS1. In summary, the results of this study suggested that HNF1α-AS1 is involved in the HNF1α-mediated regulation of P450s in the liver at both basal and drug-induced levels.

[Rs17042171 at chromosome 4q25 is associated with atrial fibrillation in the Chinese Han population from the central plains].

OBJECTIVE: To determine the correlations of single nucleotide polymorphisms (SNPs) with atrial fibrillation (AF) in the Chinese Han population from the central plains.
 Methods: A total of 168 hospitalized patients, including 56 AF and 112 controls, were recruited in this case-control study. The clinical data were obtained from the medical records. All 5 SNPs, rs337711 in KCNN2, rs11264280 near KCNN3, rs17042171 near PITX2, rs6771157 and rs6795970 in SCN10A, were genotyped using amplification refractory mutation system-polymerase chain reaction or direct sequencing. The χ2 test was used to compare categorical variables and preliminarily examine correlations between the genotype frequencies and AF. Subsequently, a logistic regression model was constructed to determine the associations between the SNPs and AF based on the above screened results. Odds ratios (ORs) and 95% confidence interval (CI) were calculated to assess the strength of the correlations. Moreover, we downloaded the genotype data from the HapMap Project for linkage disequilibrium analysis of rs17042171.
 Results: AF patients were likely to be of older age and longer left atrial diameter and had more coronary artery disease and higher hypertension compared with the control group (P<0.05). Among the 5 SNPs, the frequency distribution of genotype AA for rs17042171 was significantly different between the AF and control groups (P<0.05). After adjusting for several covariates, there was still a high risk ratio in patients with the AA genotype compared with the AC+CC genotype (OR: 5.591, 95%CI 2.176 to 14.365, P-B<0.008). Similarly, stratification analysis on the AA genotype demonstrated significant differences between rs17042171 and persistent AF. However, there were not significant correlations between AF and the control groups for the other 4 SNPs (P<0.05).
 Conclusion: Rs17042171, near PITX2 on chromosome 4q25, is associated with AF susceptibility in the Chinese Han population from the central plains, suggesting that this SNP can provide a new strategy for clinical diagnosis in AF patients.

Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin.

CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA (4- to 15-fold) by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3, above 1.8-fold) and H3 acetylation (above 2-fold) and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3, about 50%) in the CYP3A4 promoter. Rifampicin enhanced recruitment to the CYP3A4 promoter of nuclear receptor coactivator 6 (NCOA6, above 3-fold) and histone acetyltransferase p300 (p300, above 1.6-fold). Silencing NCOA6 or p300 by short-hairpin RNAs resulted in inhibition of the CYP3A4 induction as well as altered levels of H3K4me3, H3K27me3, or H3 acetylation in the CYP3A4 promoter. Knockdown of pregnane X receptor (PXR) expression not only suppressed the recruitment of NCOA6 and p300 but also abolished the changes caused by rifampicin in H3K4me3, H3K27me3, and H3 acetylation levels in the CYP3A4 promoter. Moreover, rifampicin treatment enhanced the nuclear accumulation and interactions between PXR and NCOA6/p300. In conclusion, we show that the alterations of histone modifications contribute to the PXR-mediated induction of CYP3A4 by rifampicin.

Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1.

Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression. We further showed that the transcription factor hepatocyte nuclear factor 1α (HNF1A) affects histone modifications around the UGT1A1 locus. In particular, we demonstrated that by recruiting HNF1A the cofactors mixed-lineage leukemia 1, the transcriptional coactivator p300, and nuclear receptor coactivator 6 aggregate at the UGT1A1 promoter, thereby regulating histone modifications and subsequent UGT1A1 expression. In this study, we proposed new ideas for the developmental regulation of metabolic enzymes via histone modifications, and our findings will potentially contribute to the development of age-specific therapies.

Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population.

PURPOSE: Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. METHODS: Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms. RESULTS: UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. CONCLUSIONS: Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.

Urinary heme oxygenase-1 as a potential biomarker for early diabetic nephropathy.

BACKGROUND: Our previous study showed that increases of urinary heme oxygenase-1 (uHO-1) could be a potential biomarker indicating evaluating intrarenal oxidative damage in obstructive nephropathy. Activation of oxidative stress is an important mediator of diabetic nephropathy (DN). The aim of this study was to investigate the clinical implications of uHO-1 levels in patients with type 2 diabetes. METHODS: Eighty-four type 2 diabetic patients with normoalbuminuria (n=28), microalbuminuria (n=28), and macroalbuminuria (n=28) were included in this study. Control samples were collected from healthy volunteers (n=28) who had normal albuminuria and renal function. Urine HO-1 levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: Urinary HO-1/creatinine (cr.) levels were significantly elevated in diabetic patients with microalbuminuria and macroalbuminuria compared to those in diabetic patients with normoalbuminuria (P<0.001) and control subjects (all P<0.001). In diabetic patients with normoalbuminuria, uHO-1/cr. levels were also higher than those in controls (P<0.001). Multivariate regression analyses revealed that uHO-1/cr. levels were positively correlated to urinary albumin/creatinine ratio and inversely correlated to glomerular filtration rate. Receiver operating characteristic (ROC) curve analysis of uHO-1/cr. levels for early diagnosis and detection of DN revealed that the cut-off value of uHO-1/cr. was 4.59 ng/mg (sensitivity 75%, specificity 78.6%). CONCLUSIONS: The findings of this study indicate that increases of urine HO-1 levels can be detected in patients with type 2 diabetes before the onset of significant albuminuria, and associated with renal derangement in patients with established diabetic nephropathy. Urinary HO-1 may be used as an early biomarker for diabetic renal injury.

Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis.

AIM: Recent studies indicate that pirfenidone (PFD) may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK-2). METHODS: Sixty rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and PFD-treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK-2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, α-SMA, S100A4, fibronection and E-cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected. RESULTS: In vitro, PFD significantly attenuated TGF-ß1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of α-SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-ß1-induced up-regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF-ß1, type III collagen, α-SMA, S100A4, fibronection, and increased expression of E-cadherin. CONCLUSION: These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis.

Effects of UGT1A1*6, UGT1A1*28, and ABCB1-3435C>T polymorphisms on irinotecan induced toxicity in Chinese cancer patients.

OBJECT: The aim of this study was to investigate whether UGT1A1*6/*28 or ABCB1-3435C>T polymorphisms affect irinotecan-induced severe diarrhea and neutropenia in Chinese cancer patients. METHODS: A total of 157 cancer patients was enrolled in this study and the genotypes of UGT1A1*6/*28 and ABCB1-3435C>T polymorphisms were analyzed by PCRSanger sequence. The relationship between UGT1A1*6/*28 and ABCB1-3435C>T polymorphisms and irinotecan induced severe diarrhea and neutropenia were analyzed. RESULTS AND CONCLUSION: UGT1A1*6 and UGT1A1*28 polymorphisms were associated with severe neutropenia (p = 0.025, p = 0.022, respectively) but not diarrhea (p = 0.343, p = 0.185, respectively), and ABCB1- 3435C>T polymorphism was not associated with irinotecan induced severe toxicities (p = 0.457, p = 0.161, respectively).

Comparative effectiveness of myocardial patches and intramyocardial injections in treating myocardial infarction with a MitoQ/hydrogel system.

In cardiac tissue engineering, myocardial surface patches and hydrogel intramyocardial injections represent the two primary hydrogel-based strategies for myocardial infarction (MI) treatment. However, the comparative effectiveness of these two treatments remains uncertain. Therefore, this study aimed to compare the effects of the two treatment modalities by designing a simple and reproducible hydrogel cross-linked with γ-PGA and 4-arm-PEG-SG. To improve mitochondrial damage in cardiomyocytes (CMs) during early MI, we incorporated the mitochondria-targeting antioxidant MitoQ into the hydrogel network. The hydrogel exhibited excellent biodegradability, biocompatibility, adhesion, and injectability in vitro. The hydrogel was utilized for rat MI treatment through both patch adhesion and intramyocardial injections. In vivo results demonstrated that the slow release of MitoQ peptide from the hydrogel hindered ROS production in CM, alleviated mitochondrial damage, and enhanced CM activity within 7 days, effectively inhibiting MI progression. Both hydrogel intramyocardial injections and patches exhibited positive therapeutic effects, with intramyocardial injections demonstrating superior efficacy in terms of cardiac function and structure in equivalent treatment cycles. In conclusion, we developed a MitoQ/hydrogel system that is easily prepared and can serve as both a myocardial patch and an intramyocardial injection for MI treatment, showing significant potential for clinical applications.

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.

The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by regulating chromatin accessibility and the ability of transcription factors to acquire DNA. This is achieved by recruiting associated proteins and RNA polymerases. They modify the physical contact between cis-regulatory factor elements, transcription factors, and chromatin DNA to influence transcriptional regulatory processes. Then, abnormal chromatin perturbations can impair the homeostasis of organs, tissues, and cells, leading to diseases. The review offers a comprehensive elucidation on the function and regulatory mechanism of chromatin modifiers, thereby highlighting their indispensability in the development of diseases. Furthermore, this underscores the potential of chromatin modifiers as biomarkers, which may enable early disease diagnosis. With the aid of this paper, a deeper understanding of the role of chromatin modifiers in the pathogenesis of diseases can be gained, which could help in devising effective diagnostic and therapeutic interventions.

Prenatal Lipopolysaccharide Exposure Alters Hepatic Drug-Metabolizing Enzyme Expression in Mouse Offspring via Histone Modifications.

Inflammation is a major regulator of drug-metabolizing enzymes (DMEs), therefore contributing to the interindividual variability of drug effects. However, whether prenatal inflammation affects DMEs expression in offspring remains obscure. This study investigated the effects of prenatal lipopolysaccharide (LPS) exposure on hepatic expression of inflammatory-related genes, nuclear receptors, and DMEs in offspring mice. Prenatal LPS exposure on gestational day (GD) 10 led to higher expression of NF-κB, Pxr, and Cyp2b10, while lower expression of Car, Ahr, Cyp3a11, and Ugt1a1 in postnatal day (PD) 30 offspring. However, multiple doses of LPS exposure on GD10-14 resulted in higher levels of inflammatory-related genes, Cyp1a2, and Cyp2b10, and lower levels of Pxr and Cyp3a11 in PD30 offspring liver. For PD60 offspring, decreased hepatic expression of NF-κB and IL-6, and increased expression of Pxr and Cyp3a11 were seen in single-dose LPS groups, whereas opposite results were observed in the multiple-dose LPS groups. Notably, enhanced H3K4me3 levels in the PXR response elements of the Cyp3a11 promoter were observed in the liver of PD60 offspring mice from dams treated with multiple doses of LPS during pregnancy. Overall, this study suggests that parental LPS exposure could persistently alter the hepatic expression of DMEs, and histone modifications may contribute to the long-term effects.

A Deep CNN Transformer Hybrid Model for Skin Lesion Classification of Dermoscopic Images Using Focal Loss.

Skin cancers are the most cancers diagnosed worldwide, with an estimated > 1.5 million new cases in 2020. Use of computer-aided diagnosis (CAD) systems for early detection and classification of skin lesions helps reduce skin cancer mortality rates. Inspired by the success of the transformer network in natural language processing (NLP) and the deep convolutional neural network (DCNN) in computer vision, we propose an end-to-end CNN transformer hybrid model with a focal loss (FL) function to classify skin lesion images. First, the CNN extracts low-level, local feature maps from the dermoscopic images. In the second stage, the vision transformer (ViT) globally models these features, then extracts abstract and high-level semantic information, and finally sends this to the multi-layer perceptron (MLP) head for classification. Based on an evaluation of three different loss functions, the FL-based algorithm is aimed to improve the extreme class imbalance that exists in the International Skin Imaging Collaboration (ISIC) 2018 dataset. The experimental analysis demonstrates that impressive results of skin lesion classification are achieved by employing the hybrid model and FL strategy, which shows significantly high performance and outperforms the existing work.

Identification of Atrial Fibrillation-Associated Genes ERBB2 and MYPN Using Genome-Wide Association and Transcriptome Expression Profile Data on Left-Right Atrial Appendages.

More reliable methods are needed to uncover novel biomarkers associated with atrial fibrillation (AF). Our objective is to identify significant network modules and newly AF-associated genes by integrative genetic analysis approaches. The single nucleotide polymorphisms with nominal relevance significance from the AF-associated genome-wide association study (GWAS) data were converted into the GWAS discovery set using ProxyGeneLD, followed by merging with significant network modules constructed by weighted gene coexpression network analysis (WGCNA) from one expression profile data set, composed of left and right atrial appendages (LAA and RAA). In LAA, two distinct network modules were identified (blue: p = 0.0076; yellow: p = 0.023). Five AF-associated biomarkers were identified (ERBB2, HERC4, MYH7, MYPN, and PBXIP1), combined with the GWAS test set. In RAA, three distinct network modules were identified and only one AF-associated gene LOXL1 was determined. Using human LAA tissues by real-time quantitative polymerase chain reaction, the differentially expressive results of ERBB2, MYH7, and MYPN were observed (p < 0.05). This study first demonstrated the feasibility of fusing GWAS with expression profile data by ProxyGeneLD and WGCNA to explore AF-associated genes. In particular, two newly identified genes ERBB2 and MYPN via this approach contribute to further understanding the occurrence and development of AF, thereby offering preliminary data for subsequent studies.

Epigenetic Memory Is Involved in the Persistent Alterations of Drug-Processing Genes in Adult Mice Due to PCN-Activated PXR During Early Life.

Pregnane X receptor (PXR), which can be activated by xenobiotic chemicals (including pediatric drugs), plays a key role in the regulation of drug-processing genes (DPGs). The induction of DPGs due to PXR activation may reduce therapeutic efficacy or cause toxicity. This work aims to demonstrate the impact of pregnenolone 16α-carbonitrile (PCN)-mediated PXR activation during early life on DPGs expression and drug sensitivity in adulthood, as well as the underlying mechanism. In this study, mice were sacrificed at postnatal day 60 to detect the hepatic expression of selected DPGs and histone modifications in the Cyp3a11 promoter. We found that all doses of PCN treatment (50-200 mg/kg/day) at postnatal days 5-8 resulted in persistently increased CYP2B10 expression, whereas only high doses of PCN treatment (150 and 200 mg/kg/day) persistently induced the expression of CYP3A11, 1A2, and UGT1A1. We also demonstrated that PCN treatment before postnatal day 15 had a long-term impact on the expression of CYP3A11, 2B10, ABCC4, and PAPSS2. Additionally, elevated expression of CYP3A11, SULT2A1, UGT1A1, and PAPSS2 was observed in PCN-treated groups at days 25-28. Attenuated inducibility of CYP3A11 by PCN was seen in the primary hepatocytes derived from PCN-pretreated mice. Moreover, enhanced H3K4me3 level and reduced H3K27me3 level in the PXR response elements (PXREs) of the Cyp3a11 promoter may contribute to the persistent upregulation of CYP3A11 by neonatal PCN treatment. Overall, our study suggests that PXR activation during early life could persistently alter the hepatic expression of DPGs and epigenetic memory may be an underlying mechanism in mice.

Regulation of UGT1A expression by miR-298 in human livers from the Han Chinese population and in human cell lines.

AIM: This study aimed to investigate the role of miRNAs in UGT1A regulation. MATERIALS & METHODS: Based on bioinformatic prediction results, luciferase reporter assay and cell-transfection experiments were performed to study effects of miR-298 on UGT1A expression. Correlation study was conducted in human livers. RESULTS: miR-298 overexpression reduced mRNA level of UGT1A1 and UGT1A4 in HepG2 and LS174T cells, and that of UGT1A3 and UGT1A9 in LS174T cells. miR-298 repression increased mRNA level of UGT1A4 in HepG2 and LS174T cells, and that of UGT1A1 and UGT1A3 in LS174T cells. Inverse correlations between miR-298, as well as miR-491-3p, and UGT1A3 and 1A4 mRNA levels were observed in livers. CONCLUSION: The study demonstrates that miR-298 and miR-491-3p downregulates UGT1A expression.

Suppression of miR-628-3p and miR-641 is involved in rifampin-mediated CYP3A4 induction in HepaRG cells.

AIM: This study aimed to explore the role of miRNAs in rifampin-mediated induction of CYP3A4 in HepaRG cells. MATERIALS & METHODS: Microarray was performed to determine the expression of miRNAs in rifampin-treated HepaRG cells, followed by bioinformatics and luciferase reporter gene assay to analyze miRNAs that directly target CYP3A4. Overexpression of miRNA mimics was used to study their effects on CYP3A4 induction. RESULTS: Forty-seven miRNAs were suppressed and 18 miRNAs were increased by rifampin (above twofold). MiR-628-3p and miR-641 repressed the 3'-UTR luciferase activity of CYP3A4. Overexpression of miR-628-3p and miR-641 showed significant decrease of CYP3A4 mRNA level as well as CYP3A4 induction by rifampin. CONCLUSION: miR-628-3p and miR-641 could directly target CYP3A4 and are negatively regulated in CYP3A4 induction by rifampin.

Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population.

CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.