Effect of styrene oxide and diethyl maleate on expression of cytochrome P450 family 1 and glutathione store in mouse liver

Purpose: To determine the effect of the glutathione (GSH) suppressors styrene oxide (SO) and diethyl maleate (DEM) on the hepatic expression of cytochrome P450 family 1 (Cyp1) isoforms that are related to carcinogenesis including Cyp1a1, Cyp1a2, and Cyp1b1. Methods: Seven-week-old ICR mice were intraperitoneally injected with SO (150 and 300 mg/kg/day), DEM (175 and 350 mg/kg/day), or N-acetylcysteine (NAC; 300 and 600 mg/kg/day) for 7, 14, or 28 days. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic Cyp1 expression, total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were determined. Results: ALT and AST levels were markedly increased by SO and DEM while GSH/GSSG ratio was decreased by SO in all treatments (p < 0.05), while high dose (350 mg/kg/day) DEM significantly suppressed GSH/GSSG ratio at 28 days (p < 0.05). The expressions of Cyp1a1, Cyp1a2, and Cyp1b1 were induced by SO and DEM, corresponding with induction of ethoxy/methoxy-resorufin O- dealkylase activities. Conclusion: The Cyp1 family metabolizes procarcinogens to carcinogenic DNA adducts; exposure to the industrial solvents, SO and DEM, raises the risk of carcinogenesis via GSH depletion coupled with Cyp1 induction.

Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression

ObjectsThe incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis.DesignTwo HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models.ResultsA global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis.ConclusionsThe liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection

We previously reported that the oxidised cholesterol-sensing receptor GPR183 is significantly downregulated in blood from tuberculosis (TB) patients with diabetes compared to TB patients without co-morbidities and that lower GPR183 expression in blood is associated with more severe pulmonary TB on chest-x-ray consistent with observations in dysglycemic mice. To further elucidate the role of this receptor and its endogenous high affinity agonist 7α,25-dihydroxycholesterol (7α,25-OHC) in the lung, we studied high fat diet (HFD)-induced 28 dysglycemic mice infected with M.tuberculosis. We found that the 7α,25-OHC-producing enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) were highly upregulated upon M.tuberculosis infection in the lungs of normoglycemic mice, and this was associated with increased expression of GPR183 indicative of effective recruitment of GPR183-expressing immune cells to the site of infection. We demonstrated that CYP7B1 was predominantly expressed by macrophages in the centre of TB granulomas. Expression of CYP7B1 was significantly blunted in lungs from HFD-fed dysglycemic animals and this coincided with 36 delayed recruitment of macrophages to the lung during early infection and more severe lung pathology. GPR183 deficient mice similarly had reduced macrophage recruitment during early infection demonstrating a requirement of the GPR183/oxysterol axis for macrophage infiltration into the lung in TB. Together our data demonstrate that oxidised cholesterols and GPR183 play an important role in positioning macrophages to the site of M. tuberculosis infection and that this is impaired by HFD-induced dysglycemia, adding a mechanistic explanation to the poorer TB outcomes in patients with diabetes.

Pyrrole as an Important Scaffold of Anticancer Drugs: Recent Advances

With the significant increase of patients suffering from different types of cancer, it is evident that prompt measures in the development of novel and effective agents need to be taken. Pyrrole moiety has been found in various active compounds with anti-inflammatory, antiseptic, antibacterial, lipid-lowering and anticancer properties. Recent advances in the exploration of highly active and selective cytotoxic structures containing pyrrole motifs have shown promising data for future investigations. Accordingly, this review presents an overview of recent developments in the pyrrole derivatives as anticancer agents, with a main focus towards the key moieties required for the anti-tumor activities. Pyrrole molecules comprising prominent targeting capacities against microtubule polymerization, tyrosine kinases, cytochrome p450 family 1, histone deacetylase and bcl-2 proteins were reported. In addition, several mechanisms of action, such as apoptosis, cell cycle arrest, inhibiting kinases, angiogenesis, disruption of cell migration, modulation of nuclear receptor responsiveness and others were analyzed. Furthermore, in most of the discussed cases we provided synthesis schemes of the mentioned molecules. Overall, the utilization of pyrrole scaffold for the design and synthesis of novel anticancer drugs could be a promising approach for future investigations.

Molecular and phenotypic characteristics of 15q24 microdeletion in pediatric patients with developmental disorders

Chromosome 15q24 microdeletion is a rare genetic disorder characterized by development delay, facial dysmorphism, congenital malformations, and occasional autism spectrum disorder (ASD). In this study, we identified five cases of 15q24 microdeletion using multiplex ligation-dependent probe amplification (MLPA) technology in a cohort of patients with developmental delay and/or intellectual disability. Two of these five cases had deletions that overlapped with the previously defined 1.1 Mb region observed in most reported cases. Two cases had smaller deletions (< 0.57 Mb) in the 15q24.1 low copy repeat (LCR) B-C region. They presented significant neurobehavioral features, suggesting that this smaller interval is critical for core phenotypes of 15q24 microdeletion syndrome. One case had minimal homozygous deletion of less than 0.11 Mb in the 15q24.1 LCR B-C region, which contained CYP1A1 (cytochrome P450 family 1 subfamily A member 1) and EDC3 (enhancer of mRNA decapping 3) genes, resulting in poor immunity, severe laryngeal stridor, and lower limbs swelling. This study provides additional evidence of 15q24 microdeletion syndrome with genetic and clinical findings. The results will be of significance to pediatricians in their daily practice.

The influence of excessive consumption of liquorice on phenprocoumon (Marcumar®): a case report

Here, the case of a 92-year-old female patient, who was diagnosed with atrial fibrillation and treated with phenprocoumon (Marcumar®), is reported. Pre-existing comorbidities were arterial hypertension, coronary heart disease, diabetes mellitus type 2, mild senile dementia and renal insufficiency. Despite treatment with phenprocoumon (Marcumar®), the patient experienced an ischaemic stroke. Her measured international normalized ratio (INR)-values during the months before the stroke were within the therapeutic range of 2–3, then suddenly decreased to 1.25. A retrospective inquiry failed to identify any significant changes in behaviour or therapy adherence, other than the consumption of 1.5 kg (3.3 lb) of hard-boiled candy liquorice in the days leading up to the stroke. The sudden decrease in INR-values may be explained by the influence of liquorice and its compounds on the pharmacokinetics of phenprocoumon (Marcumar®). In this context, the most important factors are the susceptibility of vitamin K antagonists to nutrition or metabolic irregularities, the influence of liquorice on the function of isoenzymes of the cytochrome P450 family that may lead to reduced bioavailability of phenprocoumon, and the influence of liquorice on peroxisome proliferator-activated receptor alpha transactivation.

CYP17 T/C (rs74357) gene polymorphism contributes to polycystic ovary syndrome susceptibility: evidence from a meta-analysis

The cytochrome P450 family 17 (CYP17) is associated with hyperandrogenism in women and the association between CYP17 gene polymorphism and the risk of polycystic ovary syndrome (PCOS) is not definitive. In order to determine whether the CYP17 T/C (rs74357) gene polymorphism is an exposure risk for PCOS, a comprehensive meta-analysis summarizing 19 studies was performed. The pooled odds ratio (OR) and the corresponding 95 % confidence interval (CI) were measured under 5 genetic models. And the stratified analyses by ethnicity, HWE, testosterone levels and BMI in controls was carried out to identify causes of substantial heterogeneity. The overall results validated that the CYP17 T/C (rs74357) gene polymorphism was significantly associated with PCOS risk in 4 genetic models. Moreover, the outcomes of subgroup analysis by ethnicity were indicated that the frequencies of C allele of the CYP17 T/C polymorphism were markedly higher in women from Asian than Caucasian (T versus C: OR 0.85, 95% CI =0.74–0.99, P < 0.05). Therefore, these findings suggested that the CYP17 T/C (rs74357) gene polymorphism played an indispensable part in increasing the susceptibility of PCOS when carrying the C allele, which proposed that the polymorphism of CYP17 gene may be a predictive factor for the risk of PCOS or an important pathway in PCOS associated metabolic and hormonal dysregulation.

Comparative Transcriptomics for Pepper (Capsicum annuum L.) under Cold Stress and after Rewarming

Cold stress has become one of the main abiotic stresses in pepper, which severely limits the growth and development of pepper. In this study, the physiological indicators and transcriptome of a cold-tolerance (CT) inbred line A188 and a cold-sensitive (CS) inbred line A122 under cold–rewarm treatments were studied; the aim of this study was to determine the potential of the key factors in pepper response to cold stress. Compared with CT, CS wilts more seriously after cold stress, with poor resilience, higher content of malondialdehyde, and lower content of soluble sugar and total chlorophyll. Moreover, during cold treatment, 7333 and 5953 differentially expressed genes (DEGs) were observed for CT and CS, respectively. These DEGs were significantly enriched in pathways related to photosynthesis, plant hormone signal transduction, and DNA damage repair. Interestingly, in addition to the widely studied transcription factors related to cold, it was also found that 13 NAC transcription factors increased significantly in the T4 group; meanwhile, the NAC8 (Capana02g003557) and NAC72 (Capana07g002219) in CT were significantly higher than those in CS under rewarming for 1 h after 72 h cold treatment. Notably, weighted gene coexpression network analysis identified four positively correlated modules and eight hub genes, including zinc finger proteins, heat shock 70 kda protein, and cytochrome P450 family, which are related to cold tolerance. All of these pathways and genes may be responsible for the response to cold and even the cold tolerance in pepper.

Incorporation of potent and selective cytochrome P450 1B1 inhibitors into Ru(II) scaffolds provides unprecedented control over enzyme activity with light

The cytochrome P450 family of enzymes (CYPs) are important targets for medicinal chemistry. Recently, CYP1B1 has emerged as a key player in chemotherapy resistance in the treatment of cancer. This enzyme is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. However, possible off-target effects, such as inhibition of liver CYPs responsible for first pass metabolism, make selective inhibition a high priority to avoid possible drug-drug interactions and toxicity. Here we describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6,000-fold improvement in potency upon activation with low energy (660 nm) light. The novel systems provide a selectivity index of 4,000–100,000 over other off-target CYPs. One key to the design was the development of novel, coordinating CYP1B1 inhibitors which suppress enzyme activity at pM concentrations in live cells. The coordinating group enforces inhibitor orientation in the active site by anchoring to the iron. The second essential component was the biologically compatible Ru(II) scaffold that cages the inhibitors before photochemical release. These Ru(II) photocages are anticipated to provide similar selectivity and control for any coordinating CYP inhibitors.