Maintenance of redox homeostasis by hypoxia-inducible factors

Oxidative phosphorylation enables cells to generate the large amounts of ATP required for development and maintenance of multicellular organisms. However, under conditions of reduced O2 availability, electron transport becomes less efficient, leading to increased generation of superoxide anions. Hypoxia-inducible factors switch cells from oxidative to glycolytic metabolism, to reduce mitochondrial superoxide generation, and increase the synthesis of NADPH and glutathione, in order to maintain redox homeostasis under hypoxic conditions

Suppressing Excimers in H‑Aggregates of Perylene Bisimide Folda-Dimer: Role of Dimer Conformation and Competing Assembly Pathways

Long-lived excitons in H-aggregates hold great promise for efficient transport of excitation energy, provided they are not scavenged by structurallly relaxed excimers. We report solution self-assembly of a perylene bisimide (PBI) folda-dimer that exhibits two distinct kinetic stages: an initial fast assembly leads to metastable aggregates with large excimer contribution that is followed by a slower growth of stable, extended H-aggregates free of excimers. Mechanistic investigations reveal an interplay of two competing aggregation pathways, where suppression of excimers is directly linked to the crossover from an isodesmic to cooperative aggregation. How the comeptition between two self-assembly pathways is influenced by the conformational flexibility of the folda-dimer is also discussed

Cooperative Self-Assembly Driven by Multiple Noncovalent Interactions: Investigating Molecular Origin and Reassessing Characterization.

International audienceCooperative interactions play a pivotal role in programmable supramolecular assembly. Emerging from a complex interplay of multiple noncovalent interactions, achieving cooperativity has largely relied on empirical knowledge. Its development as a rational design tool in molecular self-assembly requires a detailed characterization of the underlying interactions, which has hitherto been a challenge for assemblies that lack long-range order. We employ extensive one- and two-dimensional magic-angle-spinning (MAS) solid-state NMR spectroscopy to elucidate key structure-directing interactions in cooperatively bound aggregates of a perylene bisimide (PBI) chromophore. Analysis of 1H-13C cross-polarization heteronuclear correlation (CP-HETCOR) and 1H-1H double-quantum single-quantum (DQ-SQ) correlation spectra allow the identification of through-space 1H···13C and 1H···1H proximities in the assembled state and reveals the nature of molecular organization in the solid aggregates. Emergence of cooperativity from the synergistic interaction between a stronger π-stacking and a weaker interstack hydrogen-bonding is elucidated. Finally, using a combination of optical absorption, circular dichroism, and high-resolution MAS NMR spectroscopy based titration experiments, we investigate the anomalous solvent-induced disassembly of aggregates. Our results highlight the disparity between two well-established approaches of characterizing cooperativity, using thermal and good solvent-induced disassembly. The anomaly is explained by elucidating the difference between two disassembly pathways

Smoking Attenuates Transforming Growth Factor-β–Mediated Tumor Suppression Function through Downregulation of Smad3 in Lung Cancer

Epidemiological studies have demonstrated that most cases of lung cancers (85-90%) are directly attributable to cigarette smoking. Although much information has been gained about the effects of cigarette smoking on various signaling pathways causing lung cancer, nothing is known about the effect cigarette smoking on the TGF-β-induced tumor suppressor function in lung cancer. To address this issue, lung adenocarcinoma A549 and immortalized bronchial epithelial HPL1A cells were chronically treated with cigarette smoke condensate (CSC) and Dimethyl sulphoxide (DMSO, as a control) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-β-mediated transcription due to reduced expression of Smad3. Long-term CSC treatment reduced apoptosis, increased cell viability, decreased TGF-β-mediated growth inhibition, and enhanced tumorigenicity. The decrease in apoptosis is due to the up-regulation of Bcl-2, which is a downstream target of Smad3. Re-expression of Smad3 in the CSC treated cells restored TGF-β signaling, increased apoptosis and decreased cell viability and tumorigenicity. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability and increased TGF-β-mediated growth inhibition. Expression of Smad3 is lower in lung tumors of current smokers compared to that observed in never-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-β-mediated growth inhibition and apoptosis by reducing expression of Smad3