Differential Regulation of the Asthmatic Phenotype by the Aryl Hydrocarbon Receptor

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the metabolism of xenobiotics. There is growing evidence that the AhR is implicated in physiological processes such proliferation, differentiation, and immune responses. Recently, a role of the AhR in regulating allergic asthma has been suggested, but whether the AhR also regulates other type of asthma, particularly occupational/irritant-induced asthma, remains unknown. Using AhR-deficient (Ahr−/−) mice, we compared the function of the AhR in the response to ovalbumin (OVA; allergic asthma) vs. chlorine (Cl2; irritant-induced asthma) exposure. Lung inflammation and airway hyperresponsiveness were assessed 24h after exposure to Cl2 or OVA challenge in Ahr−/− and heterozygous (Ahr+/−) mice. After OVA challenge, absence of AhR was associated with significantly enhanced eosinophilia and lymphocyte influx into the airways of Ahr−/− mice. There were also increased levels of interleukin-4 (IL-4) and IL-5 in the airways. However, OVA-induced airway hyperresponsiveness was not affected. In the irritant-induced asthma model caused by exposure to Cl2, the AhR did not regulate the inflammatory response. However, absence of AhR reduced Cl2-induced airway hyperresponsiveness. Collectively, these results support a differential role for the AhR in regulating asthma outcomes in response to diverse etiological agents.

The Rumen Microbiome and Its Metabolome Together With the Host Transcriptome Act to Regulate the Cold Season Adaptation Mechanism of Grazing Tibetan Sheep

BackgroundTibetan sheep are important ruminants on the Qinghai-Tibet Plateau. They can maintain a normal life and reproduce in harsh environments under extreme cold and low oxygen. However, the molecular and metabolic mechanisms underlying the adaptability of Tibetan sheep during the cold season are still unclear. Hence, we conducted a comprehensive analysis of rumen epithelial morphology, epithelial transcriptomics, microbiology and metabolomics in a Tibetan sheep model to understand the interaction between the rumen host and microbiota and their metabolites and to explore the potential regulatory mechanism of Tibetan sheep adaptability to the cold season of the plateau. ResultsMorphological analysis showed that the ruminal muscle layer thickness and nipple width of Tibetan sheep increased significantly during the cold season ( P <0.05), and the thickness of the stratum corneum, stratum granulosa and stratum spinous of the rumen epithelium increased significantly ( P <0.05). Transcriptomics analysis showed that the differential genes were primarily enriched in the PPAR signaling pathway (ko03320), legionellosis (ko05134), phagosome (ko04145), arginine and proline metabolism (ko00330), and metabolism of xenobiotics by cytochrome P450 (ko00980). Unique differential metabolites were identified in cold season, such as cynaroside A, sanguisorbin B and tryptophyl-valine, which were mainly enriched in arachidonic acid metabolism, arachidonic acid metabolism and linolenic acid metabolism pathways, and had certain correlation with microorganisms. Integrated transcriptome-metabolome-microbiome analysis showed that epithelial gene- GSTM3 expression was upregulated in the metabolism of xenobiotics by the cytochrome P450 pathway during the cold season, leading to the downregulation of some harmful metabolites; TLR5 gene expression was upregulated and CD14 gene expression was downregulated in the legionellosis pathway during the cold season. A large number of metabolites, such as glucosidic acid and vitamin A, were produced in the steroid hormone biosynthesis and retinol metabolism pathways. ConclusionThis study comprehensively described the interaction mechanism between the rumen host and microbes and their metabolites in grazing Tibetan sheep during the cold season. Under the stimulation of the cold plateau environment, the morphological structure of the rumen epithelium of Tibetan sheep undergoes adaptive changes. Rumen epithelial genes, microbiota and metabolites act together in some key pathways related to cold season adaptation.

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxygenase. CYP1B1 contributes to the oxidative metabolism of xenobiotics, drugs, and endogenous substrates like melatonin, fatty acids, steroid hormones, and retinoids, which are involved in diverse critical cellular functions. CYP1B1 plays an important role in the pathogenesis of cardiovascular diseases, hormone-related cancers and is responsible for anti-cancer drug resistance. Inhibition of CYP1B1 activity is considered as an approach in cancer chemoprevention and cancer chemotherapy. CYP1B1 can activate anti-cancer prodrugs in tumor cells which display overexpression of CYP1B1 in comparison to normal cells. CYP1B1 involvement in carcinogenesis and cancer progression encourages investigation of CYP1B1 interactions with its ligands: substrates and inhibitors. Computational methods, with a simulation of molecular dynamics (MD), allow the observation of molecular interactions at the binding site of CYP1B1, which are essential in relation to the enzyme’s functions.

Transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumour masses

The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.

Xenobiotics: a Threat to the Health of Living Organisms

The article summarizes and analyzes the main impacts of various xenobiotics or their groups on the human body and the consequences of such exposure. The study suggests the refinements to the generally accepted classification of xenobiotics’ origins. The paper also describes the molecular mechanism of foreign substances biotransformation in a human body. The metabolism of xenobiotics differs due to their forms and types’ varieties. The factors of influence on chemicals’ metabolism are also of great importance. Individual features of the metabolism may be associated with genetic differences in the activity of metabolic enzymes. The research results further the comprehension of the exposure pathways and health impacts of the xenobiotics and their metabolites.

Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population

We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.

Association of CYP1A1, GSTM1 and GSTT1 gene polymorphisms with risk of prostate cancer in Algerian population

Background Prostate cancer is the most common cancer in the world, and its etiology involves the interaction of genetic and environmental factors. Interindividual differences observed in the metabolism of xenobiotics may be due to polymorphisms of genes encoding the detoxification enzymes. This genetic variability seems to be associated with differences in susceptibility to certain types of cancers, including prostate cancer. Our study has been made in order to investigate a possible genetic predisposition to prostate cancer in an Algerian population, through the analysis of genetic polymorphisms of three enzymes metabolizing xenobiotics namely cytochrome P450 (CYP) 1A1, glutathione S-transferase mu 1 (GSTM1) and GST theta 1 (GSTT1). Methods The current case–control study included 101 prostate cancer patients and 101 healthy controls. Genotyping of CYP1A1 T3801C polymorphisms and GSTM1/GSTT-null was made, respectively, by PCR-RFLP and multiplex PCR. Results No significantly positive associations were found for the CYP1A1 T3801C [p = 0.71, OR = 1.23 (0.56–2.72)] and GSTM1-null [p = 0.26, OR = 1.37 (0.76–2.4)] polymorphisms and prostate cancer susceptibility. However, we detect a highly significant association between GSTT1-null genotype [p = 0.03, OR = 2.03 (1.06–3.99)], GSTM1/GSTT1-double null genotype [p = 0.027, OR = 2.6; CI (1.07–6.5)] and prostate cancer risk. Furthermore, no statistically significant differences between the studied polymorphisms and tumor parameters (the Gleason score and clinical stages of aggressiveness) at diagnosis of PCa. Conclusions The risk of developing prostate cancer in Algeria does not appear to be associated with CYP1A1 T3801C genotypes and GSTM1-null, but GSTT1-null and GSTM1/GSTT1-double null genotypes increased the risk of prostate cancer.