Intracellular ROS Mediates Gas Plasma-Facilitated Cellular Transfection in 2D and 3D Cultures

This study reports the potential of cold atmospheric plasma (CAP) as a versatile tool for delivering oligonucleotides into mammalian cells. Compared to lipofection and electroporation methods, plasma transfection showed a better uptake efficiency and less cell death in the transfection of oligonucleotides. We demonstrated that the level of extracellular aqueous reactive oxygen species (ROS) produced by gas plasma is correlated with the uptake efficiency and that this is achieved through an increase of intracellular ROS levels and the resulting increase in cell membrane permeability. This finding was supported by the use of ROS scavengers, which reduced CAP-based uptake efficiency. In addition, we found that cold atmospheric plasma could transfer oligonucleotides such as siRNA and miRNA into cells even in 3D cultures, thus suggesting the potential for unique applications of CAP beyond those provided by standard transfection techniques. Together, our results suggest that cold plasma might provide an efficient technique for the delivery of siRNA and miRNA in 2D and 3D culture models

Gli proteins up-regulate the expression of basonuclin in Basal cell carcinoma.

Tumorigenesis is frequently accompanied by enhanced rRNA transcription, but the signaling mechanisms responsible for such enhancement remain unclear. Here, we report evidence suggesting a novel link between deregulated Hedgehog signaling and the augmented rRNA transcription in cancer. Aberrant activation of the Hedgehog pathway in keratinocytes is a hallmark of basal cell carcinoma (BCC), the most common cancer in light-skinned individuals. We show that Gli proteins, downstream effectors of the Hedgehog pathway, increase expression of a novel rRNA gene (rDNA) transcription factor, basonuclin, whose expression is markedly elevated in BCCs. The promoter of the human basonuclin gene contains a Gli-binding site, which is required for Gli protein binding and transcriptional activation. We show also that the level of 47S pre-rRNA is much higher in BCCs than in normal epidermis, suggesting an accelerated rRNA transcription in the neoplastic cells. Within BCC, those cells expressing the highest level of basonuclin also exhibit the greatest increase in 47S pre-rRNA, consistent with a role for basonuclin in increasing rRNA transcription in these cells. Our data suggest that Hedgehog-Gli pathway enhances rRNA transcription in BCC by increasing basonuclin gene expression

Alterations in metamemory capacity and neural correlates in a subtype of subjective cognitive decline

Backgrounds: Subjective cognitive decline (SCD), one of the important clinical indicators for preclinical Alz-heimer's disease (AD), is primarily defined as self-perceived cognitive decline without objective evidence for cognitive impairment. However, the accuracy of their self-evaluation of cognition is unclear. This study sought to investigate the capacity for self-evaluation of own cognitive performance in SCD by applying an objective metamemory paradigm. Methods: 147 individuals with SCD were classified into four subgroups by their subjective feeling of worse performance than peers or not (P+/-) and whether they have objectively slight cognitive impairment compared to normative data (S+/-). Metamemory scores, the amplitude of the low-frequency fluctuation (ALFF), fractional low-frequency fluctuation amplitude (fALFF), and cortical thickness were compared among four subgroups. Partial correlations between neuropsychological scores and neuroimaging measures were examined, controlling for age, sex, and education years. Results: SCD S+P-showed the worst performance in short-term delayed recall and the worst metamemory per-formance, indicated by the highest value in the degree of confidence of short-term delayed recall (DOC-N4) and long-term cued recall (DOC-N6) and the worst value in relative accuracy of judgments of short-term delayed recall (ROJ-N4). ALFF values in the bilateral superior medial frontal and olfactory cortices and the left superior orbitofrontal gyrus cortex were significantly higher in SCD P-compared with SCD P+ groups (all P < 0.05, FWE-corrected, cluster-wise level). A significant S x P interaction effect in the left hippocampus and middle cingulate cortex was found for the fALFF signals (all P < 0.05, FWE-corrected, cluster-wise level). Significant interaction and main effects on cortical thickness were reported. The parahippocampal and posterior cingulate cortices were significantly decreased in SCD S+P-(all P < 0.05). Conclusion: SCD S+P-showed the worst episodic memory performance, altered metamemory capacity (over-confidence and less accuracy of judgment), and altered neuroimaging measures, though they had feelings of similar performance with peers. Our results indicate that metamemory capacity is affected in a subtype of SCD with reduced cortical thickness and intensity of regional spontaneous activity in key areas for metamemory processing

Discovery and Optimization of <i>N</i>‑Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators

Selective glucocorticoid receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the glucocorticoid receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM HP-19 based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of HP-19 and designed and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of HP-19. Therein, compound B53 exhibits the best transrepression activity (IC50NF‑κB = 0.009 ± 0.001 μM) comparable with dexamethasone (IC50NF‑κB = 0.005 ± 0.001 μM) and no transactivation activity. B53 can efficiently reduce the expression of inflammatory factors IL-6, IL-1β, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, B53 is able to significantly relieve dermatitis on a mouse model via oral drug intervention

Discovery and Optimization of <i>N</i>‑Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators

Selective glucocorticoid receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the glucocorticoid receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM HP-19 based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of HP-19 and designed and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of HP-19. Therein, compound B53 exhibits the best transrepression activity (IC50NF‑κB = 0.009 ± 0.001 μM) comparable with dexamethasone (IC50NF‑κB = 0.005 ± 0.001 μM) and no transactivation activity. B53 can efficiently reduce the expression of inflammatory factors IL-6, IL-1β, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, B53 is able to significantly relieve dermatitis on a mouse model via oral drug intervention