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Background: Acute lung injury is characterized by overwhelmingly elevated PAI-1 in both lung edema fluid and the circulating system. The role of increased PAI-1, encoded by Serpine1 gene, in the regeneration of injured lung epithelium has not been understood completely. This study aimed to investigate the role of Serpine1 in the regulation of alveolar type 2 epithelial cell (AT2) fate in a humanized mouse line carrying diseased mutants (Serpine1Tg). Methods: Wild-type (wt) and Serpine1Tg AT2 cells were either cultured as monolayers or 3D alveolospheres. Colony-forming assay and total surface area of organoids were analyzed. AT1 and AT2 cells in organoids were counted by immunohistochemistry and fluorescence-activated cell sorting (FACS). To test the potential effects of elevated PAI-1 on the permeability in the epithelial monolayers, we digitized the biophysical properties of polarized AT2 monolayers grown at the air–liquid interface. Results: A significant reduction in total AT2 cells harvested in Serpine1Tg mice was observed compared with wt controls. AT2 cells harvested from Serpine1Tg mice reduced significantly over the wt controls. Spheroids formed by Serpine1Tg AT2 cells were lesser than wt control. Similarly, the corresponding surface area, a readout of re-alveolarization of injured epithelium, was markedly reduced in Serpine1Tg organoids. FACS analysis revealed a significant suppression in the number of AT2 cells, in particular, the CD44+ subpopulation, in Serpine1Tg organoids. A lesser ratio of AT1:AT2 cells in Serpine1Tg organoids was observed compared with wt cultures. There was a significant increase in transepithelial resistance but not amiloride inhibition. Conclusions: Our study suggests elevated PAI-1 in injured lungs downregulates alveolar epithelial regeneration by reducing the AT2 self-renewal, particularly in the CD44+ cells. [ABSTRACT FROM AUTHOR]

Background: Soil salt stress is a problem in the world, which turns into one of the main limiting factors hindering maize production. Salinity significantly affects root physiological processes in maize plants. There are few studies, however, that analyses the response of maize to salt stress in terms of the development of root anatomy and respiration. Results: We found that the leaf relative water content, photosynthetic characteristics, and catalase activity exhibited a significantly decrease of salt stress treatments. However, salt stress treatments caused the superoxide dismutase activity, peroxidase activity, malondialdehyde content, Na+ uptake and translocation rate to be higher than that of control treatments. The detrimental effect of salt stress on YY7 variety was more pronounced than that of JNY658. Under salt stress, the number of root cortical aerenchyma in salt-tolerant JNY658 plants was significantly higher than that of control, as well as a larger cortical cell size and a lower root cortical cell file number, all of which help to maintain higher biomass. The total respiration rate of two varieties exposed to salt stress was lower than that of control treatment, while the alternate oxidative respiration rate was higher, and the root response of JNY658 plants was significant. Under salt stress, the roots net Na+ and K+ efflux rates of two varieties were higher than those of the control treatment, where the strength of net Na+ efflux rate from the roots of JNY658 plants and the net K+ efflux rate from roots of YY7 plants was remarkable. The increase in efflux rates reduced the Na+ toxicity of the root and helped to maintain its ion balance. Conclusion: These results demonstrated that salt-tolerant maize varieties incur a relatively low metabolic cost required to establish a higher root cortical aerenchyma, larger cortical cell size and lower root cortical cell file number, significantly reduced the total respiration rate, and that it also increased the alternate oxidative respiration rate, thereby counteracting the detrimental effect of oxidative damage on root respiration of root growth. In addition, Na+ uptake on the root surface decreased, the translocation of Na+ to the rest of the plant was constrained and the level of Na+ accumulation in leaves significantly reduced under salt stress, thus preempting salt-stress induced impediments to the formation of shoot biomass. [ABSTRACT FROM AUTHOR]

The family of ten-eleven translocation dioxygenases (TETs) consists of TET1, TET2, and TET3. Although all TETs are expressed in hematopoietic tissues, only TET2 is commonly found to be mutated in age-related clonal hematopoiesis and hematopoietic malignancies. TET2 mutation causes abnormal epigenetic landscape changes and results in multiple stages of lineage commitment/differentiation defects as well as genetic instability in hematopoietic stem/progenitor cells (HSPCs). TET2 mutations are founder mutations (first hits) in approximately 40–50% of cases of TET2-mutant (TET2MT) hematopoietic malignancies and are later hits in the remaining cases. In both situations, TET2MT collaborates with co-occurring mutations to promote malignant transformation. In TET2MT tumor cells, TET1 and TET3 partially compensate for TET2 activity and contribute to the pathogenesis of TET2MT hematopoietic malignancies. Here we summarize the most recent research on TETs in regulating of both normal and pathogenic hematopoiesis. We review the concomitant mutations and aberrant signals in TET2MT malignancies. We also discuss the molecular mechanisms by which concomitant mutations and aberrant signals determine lineage commitment in HSPCs and the identity of hematopoietic malignancies. Finally, we discuss potential strategies to treat TET2MT hematopoietic malignancies, including reverting the methylation state of TET2 target genes and targeting the concomitant mutations and aberrant signals. [ABSTRACT FROM AUTHOR]

The TANK-binding kinase 1 (TBK1) is a serine/threonine kinase belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) kinase (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including activated K-RAS/N-RAS mutants. TBK1 primarily mediates IRF3/7 activation and NF-κB signaling to regulate inflammatory cytokine production and the activation of innate immunity. TBK1 is also involved in the regulation of several other cellular activities, including autophagy, mitochondrial metabolism, and cellular proliferation. Although TBK1 mutations have not been reported in human cancers, aberrant TBK1 activation has been implicated in the oncogenesis of several types of cancer, including leukemia and solid tumors with KRAS-activating mutations. As such, TBK1 has been proposed to be a feasible target for pharmacological treatment of these types of cancer. Studies suggest that TBK1 inhibition suppresses cancer development not only by directly suppressing the proliferation and survival of cancer cells but also by activating antitumor T-cell immunity. Several small molecule inhibitors of TBK1 have been identified and interrogated. However, to this point, only momelotinib (MMB)/CYT387 has been evaluated as a cancer therapy in clinical trials, while amlexanox (AMX) has been evaluated clinically for treatment of type II diabetes, nonalcoholic fatty liver disease, and obesity. In this review, we summarize advances in research into TBK1 signaling pathways and regulation, as well as recent studies on TBK1 in cancer pathogenesis. We also discuss the potential molecular mechanisms of targeting TBK1 for cancer treatment. We hope that our effort can help to stimulate the development of novel strategies for targeting TBK1 signaling in future approaches to cancer therapy. [ABSTRACT FROM AUTHOR]