Role of cytochrome P450 enzymes on alcohol/nicotine-mediated oxidative stress and cytotoxicity in monocytes/astrocytes: Implications for HIV-infected alcohol/tobacco users

Title from PDF of title page, viewed on March 13, 2013Dissertation advisor: Santosh KumarVitaIncludes bibliographic references (p. 124-143)Thesis (Ph.D.)--School of Pharmacy. University of Missouri--Kansas City, 2012Alcohol abuse is known to induce liver diseases and neurodegeneration. Chronic alcohol use during medication is known to decrease drug efficacy and increase toxicity. In addition, alcohol is known to interact with other substances of abuse, such as tobacco. Cytochrome P450 2E1 (CYP2E1), which is induced by alcohol, is mainly involved in alcohol metabolism in the liver and extra-hepatic cells in chronic users. As a result of alcohol metabolism, CYP2E1 produces reactive oxygen species (ROS), which in turn inhibits acetaldehyde dehydrogenase leading to accumulation of acetaldehyde, both of which are known to damage DNA, protein, and lipids. In addition, nicotine-metabolizing enzyme CYP2A6 and a major drug-metabolizing enzyme CYP3A4 are induced by alcohol, suggesting their role in unexpected alcohol-drug-tobacco interactions. Our central hypothesis is that CYP2A6, CYP2E1, and CYP3A4 play important role in alcohol, nicotine, and antiretroviral therapeutic (ART) drug metabolism, respectively, in monocytes/macrophages and astrocytes, leading to oxidative stress-mediated toxicity and alcohol-ART interactions. Monocytes/macrophages and astrocytes are important cell types in studying HIV-1 pathogenesis and AIDS/neuroAIDS development. Our results showed that 1) CYP2A6, CYP2E1 and CYP3A4 are induced by alcohol in U937 monocytes/macrophages, while only CYP2E1 is induced by alcohol at both mRNA and protein levels in SVGA astrocytes, 2) CYP2A6 metabolizes nicotine in U937 macrophages and SVGA astrocytes, leading to increased production of ROS, 3) CYP3A4 binds nelfinavir and other protease inhibitors (PI) and is inhibited by these PIs, 4) In both U937 monocytes and SVGA astrocytes, CYP2A6 is regulated by alcohol through oxidative stress-induced PKC/MEK/Nrf2 pathway, while CYP2E1 is regulated by oxidative stress-induced PKC/JNK/SP1 pathway, 5) In human monocytes/macrophages, CYP2E1 is induced in alcoholic as well as HIV-infected individuals. In conclusions, our findings suggested that alcohol-mediated induction of CYP2A6, CYP2E1, and CYP3A4 is responsible for increased oxidative stress, increased cytotoxicity, and decreased efficacy of ART in monocytes/macrophages and astrocytes. Since alcohol abuse and co-abuse of alcohol and tobacco are 3 times higher among HIV+ patients than that of the general population, our findings have implications in HIV-1 pathogenesis, AIDS and neuroAIDS. Our subsequent findings would help optimize ART medication and help develop alternative interventions in alcohol and tobacco-consuming HIV-infected individuals.General introduction -- General materials and methods -- Evaluation of the role of ethanol on cytochrome P450 expression -- Evaluation of the role of CYP2A6, CYP2E1 and CYP3A4 in monocytes/macrophages and astrocytes -- Mechanistic study of ethanol-mediated CYP2A6 expression: PKC-MEK-NRF2 pathway -- Mechanistic study of ethanol-induced CYP2E1 expression: PKC/JNK/SP1 pathway -- Effect of alcohol consumption on expressions of CYP2E1 and ALDH in humans -- General discussion -- Appendi

Phosphorylation of NF-κB in Cancer

The proinflammatory transcription factor nuclear factor-κB (NF-κB) has emerged as a central player in inflammatory responses and tumor development since its discovery three decades ago. In general, aberrant NF-κB activity plays a critical role in tumorigenesis and acquired resistance to chemotherapy. This aberrant NF-κB activity frequently involves several post-translational modifications of NF-κB, including phosphorylation. In this chapter, we will specifically cover the phosphorylation sites reported on the p65 subunit of NF-κB and their relationship to cancer. Importantly, phosphorylation is catalyzed by different kinases using adenosine triphosphate (ATP) as the phosphorus donor. These kinases are frequently hyperactive in cancers and thus may serve as potential therapeutic targets to treat different cancers

One-Dimensional Adapter to Rule Them All: Concepts, Diffusion Models and Erasing Applications

The prevalent use of commercial and open-source diffusion models (DMs) for text-to-image generation prompts risk mitigation to prevent undesired behaviors. Existing concept erasing methods in academia are all based on full parameter or specification-based fine-tuning, from which we observe the following issues: 1) Generation alternation towards erosion: Parameter drift during target elimination causes alternations and potential deformations across all generations, even eroding other concepts at varying degrees, which is more evident with multi-concept erased; 2) Transfer inability & deployment inefficiency: Previous model-specific erasure impedes the flexible combination of concepts and the training-free transfer towards other models, resulting in linear cost growth as the deployment scenarios increase. To achieve non-invasive, precise, customizable, and transferable elimination, we ground our erasing framework on one-dimensional adapters to erase multiple concepts from most DMs at once across versatile erasing applications. The concept-SemiPermeable structure is injected as a Membrane (SPM) into any DM to learn targeted erasing, and meantime the alteration and erosion phenomenon is effectively mitigated via a novel Latent Anchoring fine-tuning strategy. Once obtained, SPMs can be flexibly combined and plug-and-play for other DMs without specific re-tuning, enabling timely and efficient adaptation to diverse scenarios. During generation, our Facilitated Transport mechanism dynamically regulates the permeability of each SPM to respond to different input prompts, further minimizing the impact on other concepts. Quantitative and qualitative results across ~40 concepts, 7 DMs and 4 erasing applications have demonstrated the superior erasing of SPM. Our code and pre-tuned SPMs are available on the project page https://lyumengyao.github.io/projects/spm.Comment: CVPR 202

Heat transfer and system performance of a novel solar ground-source heat-pump system with borehole heat exchangers using a combined parallel and series connection

A novel BHEs is proposed that can overcome the problems associated with the low heat-transfer efficiency of borehole heat exchangers (BHEs) that are connected in series (BHEs-S) and the low heat-transfer temperature differences of BHEs that are connected in parallel (BHEs-P). The new BHE uses a combined series and parallel connection (BHEs-CSP), which can further be classified into individual in-series and in-parallel zones. A numerical model of the new BHEs-CSP is then developed to optimize the key design parameters such as borehole spacing, number of series stages, and heat-extraction methods. The results show that, with the optimal configuration, the average soil temperature with a BHEs-CSP is 6.70°C higher than for a BHE that is connected in parallel. Furthermore, the heat-transfer efficiency can be improved by 4.1% compared to BHEs that are connected in series. It is recommended that the distance between buried pipes in the series area and parallel area should be 5.25 m, and the series number of buried pipe groups should be 4. To study the overall performance of the solar-assisted ground-source heat-pump with a BHEs-CSP (SAGSHP-CSP), a TRNSYS model is developed. The results show that the optimal area- and heat-storage-ratios (for in-series zone to in-parallel zone), using SAGSHP-CSP, are 1:4 and 3:2, respectively. Under these conditions, the system coefficient of performance (SCOP) is over 5.2 and the COP and SCOP is improved by 9.8% and 13.0% compared to GSHP systems with BHEs-P. Furthermore, an improvement by 18.4% and 18.2%, compared to the GSHP system with BHEs-S, is reported

Genetic types and provenance indication of clastic amphibole in the South Yellow Sea

The main focus of studying sediment sources in marine areas is to determine the properties of clastic minerals originating from different rivers. Variations in the characteristics of clastic minerals occur due to differences in the types of source rocks within the watershed. Determining the source rock of clastic minerals in the marine area can improve the accuracy of provenance analysis. Electron probe microanalysis of 258 amphibole grains from six surface stations in the South Yellow Sea (SYS) was conducted to calculate the numerical and characteristic values of cations in the crystal structure. The results showed that amphibole in the SYS is mainly magnesiohornblende (52.2% ~ 81.4%) in the calcic amphibole subgroup, followed by tschermakite. The source rock types of amphibole are mainly different types of magmatic (ultrabasic, basic, and intermediate acidic) and metamorphic rocks. Amphibole derived from intermediate-acid intrusive rocks accounts for a large proportion (>40%). The genetic analysis of clastic amphibole in the SYS showed that most of the medium-acid invading amphibole belong to crust-mantle type, followed by mantle type. Most of the amphibole from metamorphic origins are of medium-low pressure type (± 80%). Combined with electron probe analysis of amphibole from the Huanghe River (the Yellow River, HH) and Changjiang River (the Yangtze River, CJ), the amphibole in the SYS exhibits characteristics inherited from these two rivers. The northern sea area has a strong resemblance to the sediments from the HH, while the southern area is more influenced by sediments supply from the CJ. The central area represents a mixed zone with a higher sediment supply from the HH. The clastic amphibole deduces the type of source rock in different watersheds, serving as a crucial link between the source rock, watershed, and marine area, providing a basis for provenance analysis

Reduced circulating interleukin 35 is associated with enhanced peripheral T cell function in primary biliary cholangitis

Interleukin 35 (IL-35) mediates immunosuppression of T cells in autoimmune diseases. T cells play an important role in primary biliary cholangitis (PBC) with incompletely elucidated pathogenesis. Thus, we aimed to investigate the role of IL-35 regulation on T cells in PBC patients. Fifty-one PBC patients and 28 controls were enrolled in this study. Plasma IL-35 level was measured. Purified peripheral CD4+ and CD8+ T cells were stimulated with exogenous IL-35 to investigate their functional phenotypes. IL-35-treated CD8+ T cells were cultured with human intrahepatic biliary epithelial cell line to determine the cytotoxicity of CD8+ T cells from PBC patients. Plasma IL-35 concentration was lower in PBC patients and negatively correlated with alkaline phosphatase. CD4+ T cells from PBC patients exhibited elevated transcription factor expressions and cytokine secretion, whereas CD8+ T cells produced increased cytotoxic molecules and cytokines. In vitro IL-35 stimulation suppressed the production of IL-17 and IL-22 by CD4+ T cells from PBC patients. CD8+ T cells treated with IL-35 mediated reduced target cell death in the direct contact co-culture system in PBC patients. This process was accompanied by reduced production of cytotoxic molecules and cytokines and increased expressions of immune checkpoint receptors in CD8+ T cells. Reduced circulating IL-35 might be insufficient to suppress T cell function, leading to the immune dysregulation in PBC patients

Gut microbial DL-endopeptidase alleviates Crohn's disease via the NOD2 pathway

The pattern-recognition receptor NOD2 senses bacterial muropeptides to regulate host immunity and maintain homeostasis. Loss-of-function mutations in NOD2 are associated with Crohn's disease (CD), but how the variations in microbial factors influence NOD2 signaling and host pathology is elusive. We demonstrate that the Firmicutes peptidoglycan remodeling enzyme, DL-endopeptidase, increased the NOD2 ligand level in the gut and impacted colitis outcomes. Metagenomic analyses of global cohorts (n = 857) revealed that DL-endopeptidase gene abundance decreased globally in CD patients and negatively correlated with colitis. Fecal microbiota from CD patients with low DL-endopeptidase activity predisposed mice to colitis. Administering DL-endopeptidase, but not an active site mutant, alleviated colitis via the NOD2 pathway. Therapeutically restoring NOD2 ligands with a DL-endopeptidase-producing Lactobacillus salivarius strain or mifamurtide, a clinical analog of muramyl dipeptide, exerted potent anti-colitis effects. Our study suggests that the depletion of DL-endopeptidase contributes to CD pathogenesis through NOD2 signaling, providing a therapeutically modifiable target

Interleukin-22 Might Act as a Double-Edged Sword in Type 2 Diabetes and Coronary Artery Disease

Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are both characterized by chronic low-grade inflammation. The role of Th17 and its related cytokines in T2DM and CAD is unclear. Here we investigated the serum levels of five Th17-related cytokines (IL-17, IL-22, MIP-3α, IL-9, and IL-27) in T2DM, CAD, and T2DM-CAD comorbidity patients. IL-22 was found to be elevated in all three conditions. Elevated serum IL-22 was independently associated with the incidence of T2DM and CAD. Conversely, IL-22 was found to protect endothelial cells from glucose- and lysophosphatidylcholine- (LPC-) induced injury, and IL-22R1 expression on endothelial cells was increased upon treatment with high glucose and LPC. Blocking of IL-22R1 with IL-22R1 antibody diminished the protective role of IL-22. Our results suggest that IL-22 functions as a double-edged sword in T2DM and CAD and that IL-22 may be used in the treatment of chronic inflammatory diseases such as T2DM and CAD

Barycentric convolution surfaces based on general planar polygon skeletons

© 2020 Elsevier Inc. Using barycentric coordinates for thickness interpolation, we present a novel polygonal skeleton based convolution surface approximation method with varying radii. Given the prescribed radii of an arbitrary planar polygonal skeleton, we first employ a smooth interior mean value coordinate interpolation approach to calculate the thickness at each projection position in the polygonal plane. Then a local thickness approximation method based on finite-support kernels is introduced to create an implicit surface with smoothly varying thickness. In addition, a polygon offset with different distances by winding numbers is employed to create local approximation at polygon boundaries. Our experiments show that the proposed uniform smooth thickness interpolation and local convolution approximation method can not only avoid surface wrinkles but also reduce computation cost. Moreover, our approach is insensitive to exterior thickness interpolation. Therefore smooth barycentric coordinates within a polygon can all be easily integrated into our approach