The cytochrome P450 belonging to the CYP2B subfamily has long been of great interest because it can be induced by xenobiotics. While a well known diagnostic ligand-receptor theory explains the induction of the CYP1A subfamily, the mechanism by which xenobiotics induce the CYP2B subfamily is not fully understood. Although the constitutive androstane receptor (CAR) undoubtedly plays a crucial role in the induction, many questions regarding the mechanism of CAR activation by xenobiotics have not yet been answered. It is a puzzle that many structurally-unrelated chemicals can increase the expression of the CYP2B subfamily. This may support a mechanism(s) distinct from the signaling induced by ligand-receptor binding. Indeed, phenobarbital, a typical inducer, cannot associate with CAR. Thus, no one is able to answer a fundamental question: what is the initial target of xenobiotics to produce induced expression of CYP2B enzymes? In this review, we survey the research history of CYP2B induction, list the inducers reported so far, and discuss the mechanism of induction including the target site of inducers.

Background: Pulmonary fibrosis (PF) is a devastating interstitial lung disease and characterized by an abnormal accumulation of extracellular matrix (ECM). Nintedanib (NDN) and pirfenidone are two approved therapies for PF, but their potential side-effects have been reported. Recently, the use of natural supplements for PF is attracting attention. Alpha-mangostin (α-MG) is an active xanthone-type compound isolated from the nutritious fruit mangosteen. Purpose: In the present study, the potential effect and underlying mechanism of α-MG were evaluated in bleomycin (BLM)-induced PF and activated primary lung fibroblasts (PLFs). Methods: Histopathological changes and collagen deposition were analyzed via hematoxylin-eosin staining and Masson staining, the expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (NOX4) involved in oxidative stress in lung tissues was analyzed by immunochemistry staining. The expressions of α-smooth muscle actin (α-SMA), collagen I (Col I), p-adenosine 5′-monophosphate-activated protein kinase (AMPK)/AMPK, and NOX4 were detected by Western blot, immunofluorescence or RT-PCR, and effects of α-MG on cell viability were detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Results: In vivo results demonstrated that α-MG treatment (10 mg/kg/day) significantly ameliorated BLM-induced deposition of ECM in lung tissues. Moreover, α-MG could inhibit protein expressions of α-SMA and Col I as well as its mRNA levels. In addition, α-MG also significantly inhibited transforming growth factor-β1/Smad2/3 pathway and regulated the protein expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in lung tissues. In vitro results demonstrated that α-MG significantly increased p-AMPK/AMPK but reduced the protein expression level of α-SMA and Col I as well as NOX4 in activated PLFs. Further study demonstrated that these improvement effects were significantly blocked by compound C. Conclusion: α-MG treatment significantly decreased oxidative stress in lungs partly by activating AMPK mediated signaling pathway in BLM-induced PF and activated PLFs and decreased the deposition of ECM. The present study provides pharmacological evidence to support therapeutic application of α-MG in the treatment of PF.

Abstract.In vitro tumor growth in a three-dimensional (3D) architecture has been demonstrated to play an important role in biology not only for developmental organogenesis and carcinogenesis, but also for analyses on reconstitution and maintenance in a variety of biological environments surrounding the cells. In addition to providing architectural similarity to living organisms, 3D culture with a radial flow bioreactor (RFB) can also closely mimic the living hypoxic microenvironment under which specific organogenesis or carcinogenesis occurs. The findings of the present study under the RFB culture conditions show that cancer cells underwent a shift from aerobic to hypoxic energy metabolism, in addition to protein expression to maintain the 3D structure. In RFB-cultured cells, protein stability of hypoxia-inducible factor 1 (HIF1) α, a subunit of HIF1, was increased without upregulation of its mRNA. Under these conditions, PHD2, HIF-prolyl-4-hydroxylase 2 and a HIF1 downstream enzyme, were stabilized without affecting the mRNA levels via downregulation of FK506-binding protein 8. PHD2 accumulation, which occurred concomitant with HIF1 stabilization, may have compensated for the lack of oxygen under hypoxic conditions to regulate the HIF levels. 3D-culture-induced overexpression of carbonic anhydrase (another representative HIF downstream enzyme) was found to occur independently of cell density in RFBcultured cells, suggesting that the RFB provided an adequately hypoxic microenvironment for the cultured cells. From these results, it was hypothesized that the key factors are regulatory molecules, which stabilize and degrade HIF molecules, thereby activating the HIF1 pathway under a hypoxic milieu.

Background: Coronary heart disease (CHD) rates differ markedly between the US and Japan. Fatty acid profiles have been linked to risk for CHD. Few studies have compared the plasma fatty acid composition, including trans fatty acids, in Japanese and US subjects. Methods: Fasting blood samples were taken from healthy older (>age 50) American (n = 76) and Japanese (n = 44) men, and plasma levels of 23 fatty acids were analyzed by gas chromatography and expressed as a percent of total fatty acids. Results: As expected, plasma levels of long-chain ω3 fatty acids (docosahexaenoic and eicosapentaenoic acids, DHA and EPA) were higher in Japanese men and ω6 fatty acids (e.g., arachidonic acid, AA) were lower compared with American men. Plasma levels of the major industrially-produced trans fatty acids (IP-TFAs; elaidic and linoelaidic acids) were far higher in American men, and levels of the potentially cardioprotective, primarily ruminant-derived trans fatty acid palmitoelaidic acid (POA) were higher in Japanese. Plasma levels of saturated or monounsaturated fatty acids were also higher in the American men. Conclusion: There are multiple differences in plasma fatty acid profiles between American and Japanese older men. The higher levels of DHA and EPA, along with the lower levels of the IP-TFAs, are consistent with the markedly lower risk for coronary heart disease in Japan vs. the US.

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