Intranasal oxytocin improves interoceptive accuracy and heart-beat evoked potentials in a cardiac interoceptive task.

BACKGROUND: Interoception represents perception of the internal bodily state which is closely associated with social/emotional processing and physical health in humans. Understanding the mechanism underlying interoceptive processing, particularly its modulation, is thus of great importance. Given overlap between oxytocinergic pathways and interoceptive signaling substrates in both peripheral visceral organs and the brain, intranasal oxytocin administration is a promising approach for modulating interoceptive processing. METHODS: In a double-blind, placebo-controlled, between-subject design, 72 healthy male participants performed a cardiac interoceptive task during electroencephalograph (EEG) and electrocardiograph (ECG) recording to examine whether intranasal administration of the neuropeptide oxytocin can modulate interoceptive processing. We also collected data in a resting state to examine whether we could replicate previous findings. RESULTS: Results showed that in the interoceptive task oxytocin increased interoceptive accuracy at the behavioral level which was paralleled by larger heartbeat-evoked potential amplitudes at frontocentral and central regions on the neural level. However, there were no significant effects of oxytocin on EEG or ECG during resting-state. CONCLUSIONS: These findings suggest that oxytocin may only have a facilitatory effect on interoceptive processing during task-based conditions. Our findings not only provide new insights into the modulation of interoceptive processing via targeting the oxytocinergic system but also provide proof of concept evidence for the therapeutic potential of intranasal oxytocin in mental disorders with dysfunctional interoception.

Tumor-activated neutrophils promote metastasis in breast cancer via the G-CSF-RLN2-MMP-9 axis.

The immune component of the tumor microenvironment is essential for the regulation of cancer progression. In breast cancer (BC), a patient's tumor mass is frequently infiltrated by neutrophils (tumor-associated neutrophils, TANs). Our study addressed the role of TANs and their mechanism of action in BC. Using quantitative IHC, ROC, and Cox analysis, we demonstrated that a high density of TANs infiltrating the tumor parenchyma was predictive of poor prognosis and of decreased progression-free survival of patients with BC, who underwent surgical tumor removal without previous neoadjuvant chemotherapy, in 3 different cohorts: training, validation, and independent cohorts. Conditioned medium from human BC cell lines prolonged the lifespan of healthy donor neutrophils ex vivo. Neutrophils activated by the supernatants of BC lines demonstrated an increased ability to stimulate proliferation, migration, and invasive activity of BC cells. Cytokines involved in this process were identified using antibody arrays. The relationship between these cytokines and the density of TANs was validated by ELISA and IHC in fresh BC surgical samples. It was determined that tumor-derived G-CSF significantly extended the lifespan and increased the metastasis-promoting activities of neutrophils via the PI3K-AKT and NF-κB pathways. Simultaneously, TAN-derived RLN2 promoted the migratory abilities of MCF7 cells via PI3K-AKT-MMP-9. Analysis of tumor tissues from 20 patients with BC identified a positive correlation between the density of TANs and the activation of the G-CSF-RLN2-MMP-9 axis. Finally, our data demonstrated that TANs in human BC have detrimental effects, supporting malignant cell invasion and migration.

Lung Adenocarcinoma Cells Promote Self-Migration and Self-Invasion by Activating Neutrophils to Upregulate Notch3 Expression of Cancer Cells.

Background: Invasion and migration of cancer cells play a key role in lung cancer progression and metastasis. Tumor-associated neutrophils (TANs) are related to poor prognosis in many types of cancer. However, the role of TANs in lung cancer is controversial. In this study, we investigated the effect of TANs on the invasion and migration of lung adenocarcinoma. Methods: Immunohistochemistry was performed to detect the density of infiltrating TANs and the expression of Notch3 in 100 lung adenocarcinoma tissues. Flow cytometry was used to observe the viability of neutrophils, which were isolated from healthy peripheral blood and then exposed to the supernatant of cultured lung adenocarcinoma cell lines. After treating with tumor-associated neutrophils culture supernatant, NeuCS (supernatant of cultured neutrophils), tumor cells culture supernatant, Medium (serum-free medium), respectively, the migration and invasion of the lung cancer cells before and after transfected by si-Notch3 were detected by transwell assay and wound healing assay. Kaplan-Meier plotter (http://kmplot.com/analysis/index.php?p) was used to analyze the prognostic role of the density of TANs on lung adenocarcinoma and TIMER ((http://cistrome.dfci.harvard.edu/TIMER/) was used to detect the expression of Notch3 on lung adenocarcinoma. Results: The infiltration of TANs was observed in the parenchyma and stroma of the lung adenocarcinoma, the density of TANs was positively related to the TNM stage and negatively related to the differentiation and prognosis. Notch3 expression of cancer cells was negatively related to the tumor differentiation and prognosis. Compared to quiescent neutrophils, the viability of TCCS-activated neutrophils was enhanced. Both migration and invasion of A549 and PC9 cells were significantly promoted by TANs, while after knocking down Notch3, the migration and invasion of the cancer cells were not affected by TANs. Bioinformatics analysis showed that the density of TANs and the expression of Notch3 were related to the poor prognosis. Conclusion: The results indicated that lung adenocarcinoma cells promote self-invasion and self-migration by activating neutrophils to upregulate the Notch3 expression of cancer cells. The density of infiltrating TANs may be a novel marker for the poor prognosis of lung adenocarcinoma. Targeting TANs might be a potential therapeutic strategy for lung cancer treatment.

Interaction of beta-lactam carbenes with aryl isonitriles: an unprecedented rearrangement of 2-azetidinonylidene indoles to delta-carbolinones.

The reaction of beta-lactam carbenes with aryl isonitriles proceeded in a novel [2 + 2] fashion to give high yields of 2-azetidinonylidene indoles 4, which underwent an unprecedented rearrangement to furnish 4-arylimino-delta-carbolin-2-ones 5 in almost quantitative yields. Acid catalyzed rearrangement and the subsequent hydrolysis of 2-azetidinonylidene indoles 4 produced two types of delta-carbolin-2,4-diones 10 and 11, respectively, in good to excellent yields. The photophysical study showed that both delta-carbolin-2,4-diones 10 and 11 are highly fluorescent with the fluorescent quantum yields being up to 0.43.

High nucleophilicity of cyclic amidocarbene toward aryl isocyanates, new approach to spiro[azetidinone-4,3'-indolinone] derivatives.

The nucleophilic addition of beta-lactam-4-ylidenes 2, a type of ambiphilic cyclic amidocarbene, to aryl isocyanates has been studied and their application in organic synthesis has been demonstrated. Thermolysis of spiro[beta-lactam-4,2'-oxadiazolines] 1 in the presence of aryl isocyanates afforded both N-lactam and O-lactam substituted spiro[azetidine-2-one-4,3'-indole-2'-one] derivatives 5 and 6 in the total yield of 65-86%. Upon hydrolysis, products 5 and 6 were converted into spiro[azetidine-2-one-4,3'-indole-2'-one] 9 that was analogous to known biologically active compounds.