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101.
Lisa Goedtke Heike Sprenger Ute Hofmann Felix F. Schmidt Helen S. Hammer Ulrich M. Zanger Oliver Poetz Albrecht Seidel Albert Braeuning Stefanie Hessel-Pras 《International journal of molecular sciences》2021,22(1)
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants produced by incomplete combustion of organic matter. They induce their own metabolism by upregulating xenobiotic-metabolizing enzymes such as cytochrome P450 monooxygenase 1A1 (CYP1A1) by activating the aryl hydrocarbon receptor (AHR). However, previous studies showed that individual PAHs may also interact with the constitutive androstane receptor (CAR). Here, we studied ten PAHs, different in carcinogenicity classification, for their potential to activate AHR- and CAR-dependent luciferase reporter genes in human liver cells. The majority of investigated PAHs activated AHR, while non-carcinogenic PAHs tended to activate CAR. We further characterized gene expression, protein abundancies and activities of the AHR targets CYP1A1 and 1A2, and the CAR target CYP2B6 in human HepaRG hepatoma cells. Enzyme induction patterns strongly resembled the profiles obtained at the receptor level, with AHR-activating PAHs inducing CYP1A1/1A2 and CAR-activating PAHs inducing CYP2B6. In summary, this study provides evidence that beside well-known activation of AHR, some PAHs also activate CAR, followed by subsequent expression of respective target genes. Furthermore, we found that an increased PAH ring number is associated with AHR activation as well as the induction of DNA double-strand breaks, whereas smaller PAHs activated CAR but showed no DNA-damaging potential. 相似文献
102.
Jan Haas Karen S. Frese Farbod Sedaghat-Hamedani Elham Kayvanpour Rewati Tappu Rouven Nietsch Oguz Firat Tugrul Michael Wisdom Carsten Dietrich Ali Amr Tanja Weis Torsten Niederdrnk Michael P. Murphy Thomas Krieg Marcus Drr Uwe Vlker Jens Fielitz Norbert Frey Stephan B. Felix Andreas Keller Hugo A. Katus Benjamin Meder 《International journal of molecular sciences》2021,22(4)
With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10−6). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets. 相似文献
103.
Marie Burns Lennard Ostendorf Robert Biesen Andreas Grützkau Falk Hiepe Henrik E. Mei Tobias Alexander 《International journal of molecular sciences》2021,22(5)
Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14++CD16+ monocytes, CD56+ CD16dim natural killer cells, marginal zone-like IgD+CD27+ B cells, and on CD4+ and CD8+ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies. 相似文献
104.
Luiza Ghila Thomas Aga Legy Andreas Frslev Mathisen Shadab Abadpour Joao A. Paulo Hanne Scholz Helge Rder Simona Chera 《International journal of molecular sciences》2021,22(7)
The past decade revealed that cell identity changes, such as dedifferentiation or transdifferentiation, accompany the insulin-producing β-cell decay in most diabetes conditions. Mapping and controlling the mechanisms governing these processes is, thus, extremely valuable for managing the disease progression. Extracellular glucose is known to influence cell identity by impacting the redox balance. Here, we use global proteomics and pathway analysis to map the response of differentiating human pancreatic progenitors to chronically increased in vitro glucose levels. We show that exogenous high glucose levels impact different protein subsets in a concentration-dependent manner. In contrast, regardless of concentration, glucose elicits an antipodal effect on the proteome landscape, inducing both beneficial and detrimental changes in regard to achieving the desired islet cell fingerprint. Furthermore, we identified that only a subgroup of these effects and pathways are regulated by changes in redox balance. Our study highlights a complex effect of exogenous glucose on differentiating pancreas progenitors characterized by a distinct proteome signature. 相似文献
105.
106.
Dr. Heike M. Kropp Dr. Samra Ludmann Dr. Kay Diederichs Dr. Karin Betz Dr. Andreas Marx 《Chembiochem : a European journal of chemical biology》2021,22(21):3060-3066
With increasing temperature, nucleobases in DNA become increasingly damaged by hydrolysis of exocyclic amines. The most prominent damage includes the conversion of cytosine to uracil and adenine to hypoxanthine. These damages are mutagenic and put the integrity of the genome at risk if not repaired appropriately. Several archaea live at elevated temperatures and thus, are exposed to a higher risk of deamination. Earlier studies have shown that DNA polymerases of archaea have the property of sensing deaminated nucleobases in the DNA template and thereby stalling the DNA synthesis during DNA replication providing another layer of DNA damage recognition and repair. However, the structural basis of uracil and hypoxanthine sensing by archaeal B-family DNA polymerases is sparse. Here we report on three new crystal structures of the archaeal B-family DNA polymerase from Thermococcus kodakarensis (KOD) DNA polymerase in complex with primer and template strands that have extended single stranded DNA template 5’-overhangs. These overhangs contain either the canonical nucleobases as well as uracil or hypoxanthine, respectively, and provide unprecedented structural insights into their recognition by archaeal B-family DNA polymerases. 相似文献
107.
The solubility of sulfur in chromia has been studied in H2-H2O-H2S tagged with35S at 973 and 1173 K at low oxygen and sulfur partial pressures typical for coal gasification-systems. For monocrystalline samples, it has been shown that sulfur-containing species are only present adsorbed on the surface of the specimens and can be removed by ultrasonic cleaning in acetone. The surface coverage after 4 weeks of exposure to H2-H2O-H2S was between 2.8 and 19.3% of a monolayer. In polycrystalline chromia, sulfur was located only in pores and cracks of the sample. In dense, compact areas of the specimens the solubility of sulfur was below the detection limit of autoradiography, which was estimated to be better than 0.17 ppm. 相似文献
108.
Silicon Nitride Derived from an Organometallic Polymeric Precursor: Preparation and Characterization 总被引:1,自引:0,他引:1
Wayde R. Schmidt Vijay Sukumar William J. Hurley Jr. Roberto Garcia Robert H. Doremus Leonard V. Interrante Gary M. Renlund 《Journal of the American Ceramic Society》1990,73(8):2412-2418
Partially crystalline Si3 N4 , with nanosized crystals and a specific surface area greater than 200 m2 /g, is obtained by pyrolysis of a commercially available vinylic polysilane in a stream of anhydrous NH3 to 1000°C. This polymer does not contain N initially. Crystallization to high-purity α-Si3 N4 proceeds with additional heating above 1400°C under N2 . The changes in crystallinity, powder morphology, infrared spectra, and elemental compositions, for samples annealed from 1000° to 1600°C under N2 , are consistent with an amorphous-to-crystalline transformation. Although macroscopic consolidation and local densification occur at 1400°C, volatilization and accompanying weight loss limit bulk densification. The effect of temperature on specific surface area is examined and related to the sintering process. These results are applicable to pyrolysis, decomposition, and crystallization studies of ceramics synthesized by polymeric precursor routes. 相似文献
109.
Andreas Krell Paul Blank Hongwei Ma Thomas Hutzler Manfred Nebelung 《Journal of the American Ceramic Society》2003,86(4):546-53
Sintered corundum components with submicrometer grain sizes exhibit properties which enable numerous new applications. Wet powder processing is developed to associate minimum grain sizes at highest densities with the lowest population of macrodefects. A closest ratio of powder particle size and sintered grain size is important for obtaining most fine-grained microstructures. This target was approached best by using powders with particle sizes in the range of 100–200 nm rather than with smaller nanoparticles. 相似文献
110.
Karin Yaccato Alfred Hagemeyer Andreas Lesik Anthony Volpe Henry Weinberg 《Topics in Catalysis》2004,(1):127-132
High-throughput synthesis and screening methods have been developed for the discovery of highly active lead compounds for the selective catalytic reduction as well as direct decomposition of NO in the temperature range 200–300 °C. The discovery libraries for primary screening consisted of 16 × 16 catalyst arrays on 4in. square quartz wafers. Catalysts were prepared by robotic liquid dispensing techniques and screened for catalytic activity in Symyx' scanning mass spectrometer. The scanning mass spectrometer is a fast serial screening tool that uses flat wafer catalyst surfaces, local laser heating, a scanning/sniffing nozzle and a quadrupolar mass spectrometer to compare relative catalytic activities. The feed consisted of NO/NH3 mixtures with optional O2 cofeed and Kr as the internal standard in Ar carrier gas. QMS detection allowed for tracking of H2O, N2, NO, O2, N2O and Kr. Screening protocols for catalytic materials encompassed metal precursors and carriers for supported vanadia systems, extensive doping of V2O5/TiO2, and broad screening of mixed redox metal oxides and supported base and noble metal systems. More than 500 samples could be screened in a single day. Active hits (high NO consumption accompanied by corresponding N2 production) identified in discovery libraries were re-synthesized as focus libraries for lead confirmation and further optimization. These libraries used shallower compositional gradients, for example 56 points (compositions) per ternary, with four 56-point ternaries per 4in. wafer. Broad screening ternaries were generally 8 or 15 points. The focus libraries more clearly reveal the trends and provide guidelines for secondary screening and scale-up. High conversions were achieved in scanning mass spectrometer so the scalability risk is small for the short contact time reactions. 相似文献