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Phenotyping Neurodegeneration in Man iPSCs.
The C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins' regulatory roles in genomic stability and DNA repair in HGSOC. learn more In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells. Interesting, blast through TCGA tumor cases, patients with CtBP2 genetic alternation had a significantly longer overall survival time than unaltered patients. Together, these results revealed that CtBP1/2 play a different regulatory role in genomic stability and DSBs repair pathway bias in serous ovarian cancer cells. It is possible to generate novel potential targeted therapy strategy and translational application for serous ovarian carcinoma patients with a predictable better clinical outcome.Ovarian cancer is the leading cause of gynecological malignancy-related deaths. Current therapies for ovarian cancer do not provide meaningful and sustainable clinical benefits, highlighting the need for new therapies. We show that the histone H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is overexpressed in ovarian cancer and that a higher level of DOT1L expression correlates with shorter progression-free and overall survival (OS). Pharmacological inhibition of DOT1L (EPZ-5676, EPZ004777, and SGC0946) or genetic inhibition of DOT1L attenuates the growth of ovarian cancer cells in cell culture and in a mouse xenograft model of ovarian cancer. Transcriptome-wide mRNA expression profiling shows that DOT1L inhibition results in the downregulation of genes involved in cellular biosynthesis pathways and the upregulation of proapoptotic genes. Consistent with the results of transcriptome analysis, the unbiased large-scale metabolomic analysis showed reduced levels of several metabolites of the amino acid and nucleotide biosynthesis pathways after DOT1L inhibition. DOT1L inhibition also resulted in the upregulation of the NKG2D ligand ULBP1 and subsequent increase in natural killer (NK) cell-mediated ovarian cancer eradication. Collectively, our results demonstrate that DOT1L promotes ovarian cancer tumor growth by regulating apoptotic and metabolic pathways as well as NK cell-mediated eradication of ovarian cancer and identifies DOT1L as a new pharmacological target for ovarian cancer therapy.Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.Carbon dots (CDs) have received immense attention in the last decade because they are easy-to-prepare, nontoxic, and tailorable carbon-based fluorescent nanomaterials. CDs can be categorized into three subgroups based on their morphology and chemical structure graphene quantum dots (GQDs), carbon quantum dots (CQDs), and carbonized polymer dots (CPDs). The detailed structures of the materials can vary significantly, even within the same category. This property is particularly predominant in chemically synthesized CPDs, as their formation proceeds via the polymerization-carbonization of molecules or polymer precursors. Abundant precursors endow CPDs with versatile structures and properties. A wide variety of carbon nanomaterials can be grouped under the category of CPDs because of their observed diversity. It is important to understand the precursor-dependent structural diversity observed in CPDs. Appropriate nomenclature for all classes and types of CPDs is proposed for the better utilization of these emerging materials.
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