Ligand-independent integrin ß1 signaling supports lung adenocarcinoma development.

Integrins - the principal extracellular matrix (ECM) receptors of the cell - promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin ß1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin ß1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin ß1-mediated adhesion to ECM but are dependent on integrin ß1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). These studies support a critical role for integrin ß1 in lung tumorigenesis that is mediated through constitutive, ECM binding-independent signaling involving the cytoplasmic tail.

Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles.

Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demonstrate that hyperlipidemic animals succumbed to a non-lethal dose of LPS whereas normolipidemic controls survived. Strikingly, survival of hyperlipidemic animals was restored when the nuclear import of stress-responsive transcription factors (SRTFs), Sterol Regulatory Element-Binding Proteins (SREBPs), and Carbohydrate-Responsive Element-Binding Proteins (ChREBPs) was impeded by targeting the nuclear transport checkpoint with cell-penetrating, biselective nuclear transport modifier (NTM) peptide. Furthermore, the burst of proinflammatory cytokines and chemokines, microvascular endothelial injury in the liver, lungs, heart, and kidneys, and trafficking of inflammatory cells were also suppressed. To dissect the role of nuclear transport signaling pathways we designed and developed importin-selective NTM peptides. Selective targeting of the importin α5, ferrying SRTFs and ChREBPs, protected 70-100% hyperlipidemic animals. Targeting importin ß1, that transports SREBPs, was only effective after 3-week treatment that lowered blood triglycerides, cholesterol, glucose, and averted fatty liver. Thus, the mechanism of hyperlipidemic hypersensitivity to lethal microbial inflammation depends on metabolic and proinflammatory transcription factors mobilization, which can be counteracted by targeting the nuclear transport checkpoint.

[Effects of P fertilizer on female strobilus and needle N and P nutrition of Pinus massoniana clones with different fruiting abilities.] / ç£·è‚¥å¯¹ä¸åŒç»“å®žèƒ½åŠ›é©¬å°¾æ¾æ— æ€§ç³»é›ŒçƒèŠ±é‡åŠé’ˆå¶æ°®ç£·è¥å »çš„å½±å“.

In order to realize precise fertilization and high yield management of Pinus massoniana clonal seed orchard, clones with different fruiting abilities were used as the materials. Four P fertilization levels were at 0, 400, 800 and 1600 g per plant (P0, P4, P8 and P16 respectively). Fertilization was applied before floral primordia formation and after cone picked, respectively. The effects of P fertilizer on the female strobilus of P. massoniana clones and the changes of N, P contents in needles of different positions during floral primordia formation stage and early stage of flower bud differentiation were investigated. The results showed that compared with P0, the female strobilus of P8 and P16 were significantly increased by 67.4% and 61.2% in 2018 and 28.9% and 14.1% in 2019, respectively. There was a significant negative correlation between the female strobilus with the N content and N/P, a significant positive correlation between the female strobilus and the P content in needles. The responses of N and P contents in needles to P fertilization differed in clones with different fruiting abilities. In floral primordia formation stage, the N content of clones with weak fruiting ability was high, and the N/P was 11.5-12.5, while the P content of clones with strong fruiting abilities was high, and the N/P was 9.5-10.5. During this period, the P content of most clones under P8 treatment was the highest, while the N/P was lowest. In the early stage of flower bud differentiation, the N/P of two fruiting clones was 15.3-17.0 and 13.2-15.1, respectively. The P content in upside layer was significantly higher while N/P was significantly lower than that in middle and lower layers. In conclusion, the 800 g P fertilization per plant could increase the P content and reduce the N/P of needles during the floral primordia formation stage of clones with diffe-rent fruiting abilities, which was beneficial to the formation of female strobilus and promote the yield of clone seed orchards.

Protection from Endotoxin Shock by Selective Targeting of Proinflammatory Signaling to the Nucleus Mediated by Importin Alpha 5.

Endotoxin shock is induced by LPS, one of the most potent virulence factors of the Gram-negative bacteria that cause sepsis. It remains unknown if either proinflammatory stress-responsive transcription factors (SRTFs), ferried to nucleus by importin α5, or lipid-regulating sterol regulatory element binding proteins (SREBPs), transported to the nucleus by importin ß1, mediate endotoxin shock. A novel cell-penetrating peptide targeting importin α5 while sparing importin ß1 protected 80% of animals from death in response to a high dose of LPS. This peptide suppresses inflammatory mediators, liver glycogen depletion, endothelial injury, neutrophil trafficking, and apoptosis caused by LPS. In d-galactosamine-pretreated mice challenged by 700-times lower dose of LPS, rapid death through massive apoptosis and hemorrhagic necrosis of the liver was also averted by the importin α5-selective peptide. Thus, using a new tool for selective suppression of nuclear transport, we demonstrate that SRTFs, rather than SREBPs, mediate endotoxin shock.

Dual inhibition of endothelial miR-92a-3p and miR-489-3p reduces renal injury-associated atherosclerosis.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD) patients, however, the underlying mechanisms that link CKD and CVD are not fully understood and limited treatment options exist in this high-risk population. microRNAs (miRNA) are critical regulators of gene expression for many biological processes in atherosclerosis, including endothelial dysfunction and inflammation. We hypothesized that renal injury-induced endothelial miRNAs promote atherosclerosis. Here, we demonstrate that dual inhibition of endothelial miRNAs inhibits atherosclerosis in the setting of renal injury. METHODS: Aortic endothelial miRNAs were analyzed in apolipoprotein E-deficient (Apoe-/-) mice with renal damage (5/6 nephrectomy, 5/6Nx) by real-time PCR. Endothelial miR-92a-3p and miR-489-3p were inhibited by locked-nucleic acid (LNA) miRNA inhibitors complexed to HDL. RESULTS: Renal injury significantly increased endothelial miR-92a-3p levels in Apoe-/-;5/6Nx mice. Dual inhibition of miR-92a-3p and miR-489-3p in Apoe-/-;5/6Nx with a single injection of HDL + LNA inhibitors significantly reduced atherosclerotic lesion area by 28.6% compared to HDL + LNA scramble (LNA-Scr) controls. To examine the impact of dual LNA treatment on aortic endothelial gene expression, total RNA sequencing was completed, and multiple putative target genes and pathways were identified to be significantly altered, including the STAT3 immune response pathway. Among the differentially expressed genes, Tgfb2 and Fam220a were identified as putative targets of miR-489-3p and miR-92a-3p, respectively. Both Tgfb2 and Fam220a were significantly increased in aortic endothelium after miRNA inhibition in vivo compared to HDL + LNA-Scr controls. Furthermore, Tgfb2 and Fam220a were validated with gene reporter assays as direct targets of miR-489-3p and miR-92a-3p, respectively. In human coronary artery endothelial cells, over-expression and inhibition of miR-92a-3p decreased and increased FAM220A expression, respectively. Moreover, miR-92a-3p overexpression increased STAT3 phosphorylation, likely through direct regulation of FAM220A, a negative regulator of STAT3 phosphorylation. CONCLUSIONS: These results support endothelial miRNAs as therapeutic targets and dual miRNA inhibition as viable strategy to reduce CKD-associated atherosclerosis.