Thiol-Based Antioxidants and the Epithelial/Mesenchymal Transition in Cancer.

Significance: The epithelial/mesenchymal transition (EMT) is commonly associated with tumor metastasis. Oxidative and nitrosative stress is maintained in cancer cells and is involved in the EMT. Cancer cells are endowed with high levels of enzymatic and nonenzymatic antioxidants, which counteract the effects of oxidative and nitrosative stress. Thiol-based antioxidant systems such as the thioredoxin/thioredoxin reductase (Trx/TrxR) and glutathione/glutaredoxin (GSH/Grx) are continually active in cancer cells, while the thioredoxin-interacting protein (Txnip), the negative regulator of the Trx/TrxR system, is downregulated. Recent Advances: Trx/TrxR and GSH/Grx systems play a major role in maintaining EMT signaling and cancer cell progression. Critical Issues: Enhanced stress conditions stimulated in cancer cells inhibit EMT signaling. The elevated expression levels of the Trx/TrxR and GSH/Grx systems in these cells provide the antioxidant protection necessary to guarantee the occurrence of the EMT. Future Directions: Elevation of the intracellular reactive oxygen species and nitric oxide concentrations in cancer cells has been viewed as a promising strategy for elimination of these cells. The development of inhibitors of GSH synthesis and of the Trx/TrxR system together with genetic-based strategies to enhance Txnip levels may provide the necessary means to achieve this goal. Antioxid. Redox Signal. 36, 1037-1050.

Effects of renal denervation on cardiovascular, metabolic and renal functions in streptozotocin-induced diabetic rats.

Diabetes promotes renal sympathetic hyperactivity, autonomic imbalance, and cardiovascular and renal dysfunction. Bilateral renal denervation (BRD) has emerged as a treatment for diabetes; however, the mechanisms that underlie the beneficial effects of BRD are unknown. AIMS: The present study evaluated the effects of BRD on autonomic, cardiovascular, metabolic, and renal function in streptozotocin-diabetic rats. MAIN METHODS: Wistar rats were separated into three experimental groups: control (CTR), diabetic (DM), and diabetic that underwent BRD (DM BRD). BRD was performed two weeks after STZ-diabetes induction, the experiments were performed four weeks after DM induction. This study evaluated sympathetic vasomotor nerve activity in different territories (renal, lumbar and splanchnic), arterial baroreceptor reflex, metabolic and renal function. KEY FINDINGS: BRD significantly reduced glycemia, glycosuria, albuminuria, and SGLT2 gene expression in the kidney in DM rats. Renal sympathetic nerve activity (rSNA) was significantly increased and splanchnic sympathetic nerve activity (sSNA) was significantly decreased in DM rats, without changes in lumbar sympathetic nerve activity (lSNA). BRD was able to normalize sSNA and significantly increase lSNA in DM rats compared to control rats. Additionally, cardiac baroreceptor sensitivity was impaired in DM rats, and BRD significantly improved baroreflex sensitivity. SIGNIFICANCE: Our data suggest that renal nerves play an important role in autonomic, cardiovascular, and renal dysfunction in STZ-DM rats. Thus, sympathetic renal hyperactivity should be considered a possible therapeutic target in diabetic patients.

BMP-2 and -4 produced by vascular smooth muscle cells from atherosclerotic lesions induce monocyte chemotaxis through direct BMPRII activation.

OBJECTIVE: Monocytes and macrophages, together with vascular smooth muscle cells (VSMCs), play key roles at all stages of atherogenesis. There is also growing evidence that BMP signaling is involved in vascular diseases, including atherosclerosis. Here we evaluate the role played by the BMP agonist/antagonist axis in monocyte recruitment during atherogenesis. METHODS AND RESULTS: Using ApoE-/- mice and BMPs, Gremlin and BMPRII siRNAs we show that BMPs (2 and 4) and their antagonist Gremlin are co-expressed in murine and human atherosclerotic vessels. Additionally, those genes are co-expressed and upregulated in cultured vascular smooth muscle cells early in atherosclerosis formation in ApoE-/- mice. Furthermore, we demonstrate that BMP-2 and -4 produced in atherosclerotic VSMCs promote, whereas Gremlin inhibits, monocyte chemoattraction. Finally, we demonstrate that chemotaxis induction occurs through direct BMP receptor II (BMPRII) activation. CONCLUSION: These findings suggest that the balance between BMPs (2 and 4) and Gremlin levels modulate crosstalk processes between vascular and immune cells and ultimately the homeostasis in normal vasculature. They also indicate that under pro-atherogenic conditions, BMP signaling prevails, favoring monocyte recruitment and inflammation. Manipulation of BMP signaling may enable the identification of novel molecular approaches for preventing, stabilizing, and reverting atherosclerosis.