Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System

Bivalent proximity-inducing compounds represent a novel class of small molecule therapeutics with exciting potential and new challenges. The most prominent examples of such compounds are utilized in targeted protein degradation where E3 ligases are hijacked to recruit a substrate protein to the proteasome via ubiquitination. In this review we provide an overview of the current state of E3 ligases used in targeted protein degradation, their respective ligands as well as challenges and opportunities that present themselves with these compounds

Control of absolute stereochemistry in transition-metal-catalyzed hydrogen borrowing reactions

Hydrogen borrowing catalysis represents a powerful method for the alkylation of amine or enolate nucleophiles with unactivated alcohols. This approach relies upon a catalyst which can mediate a strategic series of redox events, enabling the formation of C–C and C–N bonds and producing water as the sole by‐product. In the majority of cases these reactions have been employed to target achiral or racemic products. In contrast, the focus of this minireview is upon hydrogen borrowing catalyzed reactions in which the absolute stereochemical outcome of the process can be controlled. Asymmetric hydrogen borrowing catalysis is rapidly emerging as a powerful approach for the synthesis of enantioenriched amine and carbonyl containing products and examples involving both C–N and C–C bond formation are presented. A variety of different approaches are discussed including use of chiral auxiliaries, asymmetric catalysis and enantiospecific processes

Long-Term Exposure to Nanosized TiO2 Triggers Stress Responses and Cell Death Pathways in Pulmonary Epithelial Cells

There is little in vitro data available on long-term effects of TiO2 exposure. Such data are important for improving the understanding of underlying mechanisms of adverse health effects of TiO2 . Here, we exposed pulmonary epithelial cells to two doses (0.96 and 1.92 µg/cm2 ) of TiO2 for 13 weeks and effects on cell cycle and cell death mechanisms, i.e., apoptosis and autophagy were determined after 4, 8 and 13 weeks of exposure. Changes in telomere length, cellular protein levels and lipid classes were also analyzed at 13 weeks of exposure. We observed that the TiO2 exposure increased the fraction of cells in G1-phase and reduced the fraction of cells in G2-phase, which was accompanied by an increase in the fraction of late apoptotic/necrotic cells. This corresponded with an induced expression of key apoptotic proteins i.e., BAD and BAX, and an accumulation of several lipid classes involved in cellular stress and apoptosis. These findings were further supported by quantitative proteome profiling data showing an increase in proteins involved in cell stress and genomic maintenance pathways following TiO2 exposure. Altogether, we suggest that cell stress response and cell death pathways may be important molecular events in long-term health effects of TiO

Long-Term Exposure to Nanosized TiO2 Triggers Stress Responses and Cell Death Pathways in Pulmonary Epithelial Cells

There is little in vitro data available on long-term effects of TiO2 exposure. Such data are important for improving the understanding of underlying mechanisms of adverse health effects of TiO2 . Here, we exposed pulmonary epithelial cells to two doses (0.96 and 1.92 µg/cm2 ) of TiO2 for 13 weeks and effects on cell cycle and cell death mechanisms, i.e., apoptosis and autophagy were determined after 4, 8 and 13 weeks of exposure. Changes in telomere length, cellular protein levels and lipid classes were also analyzed at 13 weeks of exposure. We observed that the TiO2 exposure increased the fraction of cells in G1-phase and reduced the fraction of cells in G2-phase, which was accompanied by an increase in the fraction of late apoptotic/necrotic cells. This corresponded with an induced expression of key apoptotic proteins i.e., BAD and BAX, and an accumulation of several lipid classes involved in cellular stress and apoptosis. These findings were further supported by quantitative proteome profiling data showing an increase in proteins involved in cell stress and genomic maintenance pathways following TiO2 exposure. Altogether, we suggest that cell stress response and cell death pathways may be important molecular events in long-term health effects of TiO

Long-Term Exposure to Nanosized TiO2 Triggers Stress Responses and Cell Death Pathways in Pulmonary Epithelial Cells

There is little in vitro data available on long-term effects of TiO2 exposure. Such data are important for improving the understanding of underlying mechanisms of adverse health effects of TiO2 . Here, we exposed pulmonary epithelial cells to two doses (0.96 and 1.92 µg/cm2 ) of TiO2 for 13 weeks and effects on cell cycle and cell death mechanisms, i.e., apoptosis and autophagy were determined after 4, 8 and 13 weeks of exposure. Changes in telomere length, cellular protein levels and lipid classes were also analyzed at 13 weeks of exposure. We observed that the TiO2 exposure increased the fraction of cells in G1-phase and reduced the fraction of cells in G2-phase, which was accompanied by an increase in the fraction of late apoptotic/necrotic cells. This corresponded with an induced expression of key apoptotic proteins i.e., BAD and BAX, and an accumulation of several lipid classes involved in cellular stress and apoptosis. These findings were further supported by quantitative proteome profiling data showing an increase in proteins involved in cell stress and genomic maintenance pathways following TiO2 exposure. Altogether, we suggest that cell stress response and cell death pathways may be important molecular events in long-term health effects of TiO

Improved riboflavin production with Ashbya gossypii from vegetable oil based on 13 C metabolic network analysis with combined labeling analysis by GC/MS, LC/MS, 1D, and 2D NMR

The fungus Ashbya gossypii is an important industrial producer of riboflavin, i.e. vitamin B-2. In order to meet the constantly increasing demands for improved production processes, it appears essential to better understand the underlying metabolic pathways of the vitamin. Here, we used a highly sophisticated set-up of parallel C-13 tracer studies with labeling analysis by GC/MS, LC/MS, 1D, and 2D NMR to resolve carbon fluxes in the overproducing strain A. gossypii B2 during growth and subsequent riboflavin production from vegetable oil as carbon source, yeast extract, and supplemented glycine. The studies provided a detailed picture of the underlying metabolism. Glycine was exclusively used as carbon-two donor of the vitamin's pyrimidine ring, which is part of its iso-alloxazine ring structure, but did not contribute to the carbon-one metabolism due to the proven absence of a functional glycine cleavage system. The pools of serine and glycine were closely connected due to a highly reversible serine hydroxymethyltransferase. Transmembrane formate flux simulations revealed that the one-carbon metabolism displayed a severe bottleneck during initial riboflavin production, which was overcome in later phases of the cultivation by intrinsic formate accumulation. The transiently limiting carbon-one pool was successfully replenished by time-resolved feeding of small amounts of formate and serine, respectively. This increased the intracellular availability of glycine, serine, and formate and resulted in a final riboflavin titer increase of 45%

Colorectal cancer screening with repeated fecal immunochemical test versus sigmoidoscopy: baseline results from a randomized trial

Background and aims: The comparative effectiveness of sigmoidoscopy and fecal immunochemical testing (FIT) for colorectal cancer (CRC) screening is unknown. Methods: Individuals aged 50-74 years living in South-East Norway were randomly invited between 2012 and 2019 to either once-only flexible sigmoidoscopy or FIT screening every second year. Colonoscopy was recommended after sigmoidoscopy if any polyp ≥10 mm, ≥ three adenomas, any advanced adenomas, or CRC was found or subsequent to FIT > 15 μg hemoglobin/g feces. Data for this report were obtained after complete recruitment in both groups and included two full FIT rounds and part of the third round. Outcome measures were participation, neoplasia detection, and adverse events. Age-standardized detection rates and age-adjusted odds ratios (OR) were calculated. Results: We included 139,291 individuals; 69,195 randomized to sigmoidoscopy and 70,096 to FIT. Participation rate was 52% for sigmoidoscopy, 58% in the first FIT round and 68% for three cumulative FIT rounds. Compared to sigmoidoscopy, detection rate for CRC was similar in the first FIT round (0.25% vs 0.27%, OR 0.92, 95% CI 0.75-1.13), but higher after three FIT rounds (0.49% vs 0.27%, OR 1.87, 95% CI 1.54-2.27). Advanced adenoma detection rate was lower in the first FIT round compared to sigmoidoscopy, 1.4% vs 2.4% (OR 0.57, 95% CI 0.53-0.62), but higher after three cumulative FIT rounds, 2.7% vs 2.4% (OR 1.14, 95% CI 1.05-1.23). There were 33 (0.05%) serious adverse events in the sigmoidoscopy group compared to 47 (0.07%) in the FIT group (p =.13). Conclusion: Participation was higher and more CRC and advanced adenomas were detected with repeated FIT compared to sigmoidoscopy. The risk of perforation and bleeding was comparable. Clinicaltrials.gov (NCT01538550)