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Our group has recently developed an α-fluoroamine synthesis using dioxaphospholenes derived from various 1,2-diketones and the dealkylation-resistant phosphoramidite as carbene surrogates, enabling the formal insertion into the N–F bond of (PhSO2)2NF. This full account presents the scope and limitations in terms of the reactivity and the site selectivity; these were rationalized through computational analysis. In addition, the efforts to broaden the synthetic utility of the current process by incorporating other nitrogen nucleophiles and halogen electrophiles are described.

Representative H&E images of Ahnak-/- and WT lungs in embryonic day 18.5 and postnatal day 1.

AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak−/− mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak−/− mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak−/− mice developed lung tumors, and Ahnak−/− mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak−/− lungs, and the depletion of AMs in Ahnak−/− lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer.Implications: The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. Mol Cancer Res; 16(8); 1287–98. ©2018 AACR.

Supplementary figure legends

The synthesis of α-fluoroamines was achieved via deoxygenative geminal fluorosulfonimidation of 1,2-diketones using a dealkylation-resistant phosphoramidite under mild conditions that require neither excess reagents nor transition metal catalysts.

A deoxygenative geminal fluorosulfonimidation of 1,2-diketones was achieved for the synthesis of tetrasubstituted α-fluoroamines under mild conditions. In this study, a transition metal-free formal N-F insertion of

AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak−/− mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak−/− mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak−/− mice developed lung tumors, and Ahnak−/− mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak−/− lungs, and the depletion of AMs in Ahnak−/− lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer. Implications: The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. Mol Cancer Res; 16(8); 1287–98. ©2018 AACR.

Introduction Exercise-induced apelin as a myokine is believed to play a role in the improvement of type 2 diabetes mellitus (T2DM) and capillarization. In this study, we evaluated the association between exercise-induced apelin and muscle capillarization. Methods Zucker rats underwent a treadmill exercise program. Body composition, muscle strength, muscle size, muscle capillarization, and insulin resistance (homeostatic model assessment [HOMA-IR]) were measured. Apelin levels of skeletal muscle and plasma were then analyzed. Results Exercise improved body composition (P

Hes6 is a member of the hairy-enhancer of split homolog (Hes) family of transcription factors and interacts with other Hes family genes. During development, Hes genes are expressed in neural stem cells and progenitor cells. However, the role of Hes6 in adult hippocampal neurogenesis remains unclear. We therefore investigated the effects of Hes6 on adult hippocampal neurogenesis, by comparing Hes6 knockout and wild-type mice. To this end, we immunostained for markers of neural stem cells and progenitor cells (nestin), proliferating cells (Ki67), post-mitotic neuroblasts and immature neurons (doublecortin, DCX), mature neuronal cells (NeuN), and astrocyte (S100β). We also injected 5-bromo-2'-deoxyuridine (BrdU) to trace the fate of mitotic cells. Nestin- and Ki67-positive proliferating cells did now show any significant differences between wild and knockout groups. Hes6 knockout negatively affects neuroblast differentiation based on DCX immunohistochemistry. On the contrary, the ratio of the BrdU and NeuN double-positive cells did not show any significance, even though it was slightly higher in the knockout group. These results suggest that Hes6 is involved in the regulation of neuroblast differentiation during adult neurogenesis, but does not influence integration into mature neurons.

We compare comprehensive quantitative profiling of lipids at the molecular level from skeletal muscle tissues (gastrocnemius and soleus) of Zucker diabetic fatty rats and Zucker lean control rats during treadmill exercise by nanoflow liquid chromatography–tandem mass spectrometry. Because type II diabetes is caused by decreased insulin sensitivity due to excess lipids accumulated in skeletal muscle tissue, lipidomic analysis of muscle tissues under treadmill exercise can help unveil the mechanism of lipid-associated insulin resistance. In total, 314 lipid species, including phospholipids, sphingolipids, ceramides, diacylglycerols (DAGs), and triacylglycerols (TAGs), were analyzed to examine diabetes-related lipid species and responses to treadmill exercise. Most lysophospholipid levels increased with diabetes. While DAG levels (10 from the gastrocnemius and 13 from the soleus) were >3-fold higher in diabetic rats, levels of most of these decreased after exercise in soleus but not in gastrocnemius. Levels of 5 highly abundant TAGs (52:1 and 54:3 in the gastrocnemius and 48:2, 50:2, and 52:4 in the soleus) displaying 2-fold increases in diabetic rats decreased after exercise in the soleus but not in the gastrocnemius in most cases. Thus, aerobic exercise has a stronger influence on lipid levels in the soleus than in the gastrocnemius in type 2 diabetic rats.

Exercise-induced apelin as a myokine is believed to play a role in the improvement of type 2 diabetes mellitus (T2DM) and capillarization. In this study, we evaluated the association between exercise-induced apelin and muscle capillarization.Zucker rats underwent a treadmill exercise program. Body composition, muscle strength, muscle size, muscle capillarization, and insulin resistance (homeostatic model assessment [HOMA-IR]) were measured. Apelin levels of skeletal muscle and plasma were then analyzed.Exercise improved body composition (P 0.05), HOMA-IR (P 0.05), and grip strength (P 0.001). In the soleus, the fiber size of T2DM was decreased (P 0.001), but it increased in fiber size and capillarization after exercise (P 0.001) occurred. We identified an increase in plasma apelin (P 0.05) and a decrease in soleus apelin (P 0.01), as well as an association between soleus apelin and angiogenesis (P 0.01).A role for exercise-induced apelin in improving metabolism indicates the possibility of a new drug target for the treatment of metabolic diseases and repairing skeletal muscle damage. Muscle Nerve 56: 1155-1163, 2017.