Gut-Lung Dysbiosis Accompanied by Diabetes Mellitus Leads to Pulmonary Fibrotic Change through the NF-κB Signaling Pathway.

Growing evidence shows that the lungs are an unavoidable target organ of diabetic complications. However, the pathologic mechanisms of diabetic lung injury are still controversial. This study demonstrated the dysbiosis of the gut and lung microbiome, pulmonary alveolar wall thickening, and fibrotic change in streptozotocin-induced diabetic mice and antibiotic-induced gut dysbiosis mice compared with controls. In both animal models, the NF-κB signaling pathway was activated in the lungs. Enhanced pulmonary alveolar well thickening and fibrotic change appeared in the lungs of transgenic mice expressing a constitutively active NF-κB mutant compared with wild type. When lincomycin hydrochloride-induced gut dysbiosis was ameliorated by fecal microbiota transplant, enhanced inflammatory response in the intestine and pulmonary fibrotic change in the lungs were significantly decreased compared with lincomycin hydrochloride-treated mice. Furthermore, the application of fecal microbiota transplant and baicalin could also redress the microbial dysbiosis of the gut and lungs in streptozotocin-induced diabetic mice. Taken together, these data suggest that multiple as yet undefined factors related to microbial dysbiosis of gut and lungs cause pulmonary fibrogenesis associated with diabetes mellitus through an NF-κB signaling pathway.

CNTF and Nrf2 Are Coordinately Involved in Regulating Self-Renewal and Differentiation of Neural Stem Cell during Embryonic Development.

There is high risk of fetal neurodevelopmental defects in pregestational diabetes mellitus (PGDM). However, the effective mechanism of hyperglycemia-induced neurodevelopmental negative effects, including neural stem cell self-renewal and differentiation, still remains obscure. Neuropoietic cytokines have been shown to play a vital part during nervous system development and in the coordination of neurons and gliocytes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) dysfunction might be related to a reduction of self-protective response in brain malformation induced by hyperglycemia. We therefore evaluated the role of Nrf2 and neuropoietic cytokines in fetal neurodevelopmental defects induced by PGDM and determined the mechanisms involved. Our data reveal that PGDM dramatically impairs the developmental switch of neural stem cells from neurogenesis to gliogenesis, principally under the cooperative mediation of neuropoietic cytokine CNTF and Nrf2 antioxidative signaling. This indicates that CNTF and Nrf2 could be potentially used in the prevention or therapy of neurodevelopmental defects of PGDM offspring.

Negative impact of hyperglycaemia on mouse alveolar development.

Diabetes mellitus in pregnancy has been known to affect the embryonic development of various systems, including cardiovascular and nervous systems. However, whether this disease could have a negative impact on embryonic respiratory system remains controversial. In this study, we demonstrated that pregestational diabetes mellitus (PGDM)-induced defects in lung development in mice are mainly characterized by the changes in the morphological structure of the lung. Immunostaining and Western blotting showed that proliferation increased and apoptosis decreased in PGDM. Hyperglycaemia caused pulmonary tissue fibrationas manifested by an increase in Masson staining and decorin expression in PGDM lungs, and the immunofluorescent pro-SPC+ type II pulmonary epithelial cell number was decreased. The alteration of pulmonary epithelial cell differentiation might be due to hyperglycaemia-activated Wnt signalling and suppressed GATA6 expression in PGDM mouse lung tissues and MLE-12 cells. The treatment of MLE-12 cells with high glucose in the presence/absence of XAV939 or su5402 further proved that hyperglycaemia suppressed the expression of GATA6 and pro-SPC by activating Wnt signalling and induced the expression of decorin, α-SMA and TGF-ß by activating Fgf signalling. Therefore, in this study, we revealed that hyperglycemia induced dysfunctional pulmonary cell apoptosis and proliferation, as well as pulmonary myofibroblast hyperplasia, which contributed to the formation of aberrant structure of alveolar walls. Furthermore, the hyperglycaemia also inhibited the differentiation of pulmonary epithelial cells through the canonical Wnt and Fgf signalling, and the alteration of Fgf and Wnt signalling activated TGF-ß, which would promote the AECII EMT process.

Baicalin administration attenuates hyperglycemia-induced malformation of cardiovascular system.

In this study, the effects of Baicalin on the hyperglycemia-induced cardiovascular malformation during embryo development were investigated. Using early chick embryos, an optimal concentration of Baicalin (6 µM) was identified which could prevent hyperglycemia-induced cardiovascular malformation of embryos. Hyperglycemia-enhanced cell apoptosis was reduced in embryos and HUVECs in the presence of Baicalin. Hyperglycemia-induced excessive ROS production was inhibited when Baicalin was administered. Analyses of SOD, GSH-Px, MQAE and GABAA suggested Baicalin plays an antioxidant role in chick embryos possibly through suppression of outwardly rectifying Cl(-) in the high-glucose microenvironment. In addition, hyperglycemia-enhanced autophagy fell in the presence of Baicalin, through affecting the ubiquitin of p62 and accelerating autophagy flux. Both Baicalin and Vitamin C could decrease apoptosis, but CQ did not, suggesting autophagy to be a protective function on the cell survival. In mice, Baicalin reduced the elevated blood glucose level caused by streptozotocin (STZ). Taken together, these data suggest that hyperglycemia-induced embryonic cardiovascular malformation can be attenuated by Baicalin administration through suppressing the excessive production of ROS and autophagy. Baicalin could be a potential candidate drug for women suffering from gestational diabetes mellitus.