Explore the vast range of titles available.

Doxorubicin (Dox) can induce endotheliotoxicity and damage the vascular endothelium (VE). The most principle mechanism might be excess reactive oxygen species (ROS) generation. Nevertheless, the characteristics of ROS generation, downstream mechanisms, and target organelles in Dox-induced endotheliotoxicity have yet to be elucidated. In order to explore the related problems, the VE injury models were established in mice and human umbilical vein endothelial cells (HUVECs) by Dox-induced endotheliotoxicity. Results showed that the activities of lactate dehydrogenase (LDH) and creatine kinase of mice's serum increased after injected Dox. The thoracic aortic strips' endothelium-dependent dilation was significantly impaired, seen noticeable inflammatory changes, and brown TUNEL-positive staining in microscopy. After Dox-treated, HUVECs viability lowered, LDH and caspase-3 activities, and apoptotic cells increased. Both intracellular/mitochondrial ROS generation significantly increased, and intracellular ROS generation lagged behind mitochondria. HUVECs treated with Dox plus ciclosporin A (CsA) could basically terminate ROS burst, but plus edaravone (Eda) could only delay or inhibit, but could not completely cancel ROS burst. Meanwhile, the expression of endothelial nitric oxide synthase (eNOS) decreased, especially phosphorylation of eNOS significantly. Then nitric oxide content decreased, the mitochondrial function was impaired, mitochondrial membrane potential (MMP) impeded, mitochondrial swelled, mitochondrial permeability transition pore (mPTP) was opened, and cytochrome C was released from mitochondria into the cytosol. Dox produces excess ROS in the mitochondria, thereby weakens the MMP, opens mPTP, activates the ROS-induced ROS release mechanism, induces ROS burst, and leads to mitochondrial dysfunction, which in turn damages VE. Therefore, interrupting any step of the cycles, as mentioned above can end the related vicious cycle and prevent the occurrence and development of injury.

The global prevalence of gestational diabetes mellitus (GDM) is increasing, posing significant health risks to both mothers and infants. Visceral adipose tissue-derived serine protease inhibitor (Vaspin) has been identified as a potential insulin sensitizer that may mitigate insulin resistance (IR). However, the related mechanism by which Vaspin improves IR in patients with GDM remains unclear. This study aims to investigate whether Vaspin ameliorates IR in GDM via modulation of the ROS/eNOS/NO signaling pathway. Clinical samples from 58 pregnant women were collected and categorized into GDM and control (G) groups. Binary logistic regression analysis revealed significant associations between Vaspin, IR, and GDM. A GDM rat model was established using 50 female Sprague-Dawley (SD) rats, divided into GDM and G groups. Fasting blood glucose (FBG), fasting insulin (FINS), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) levels were measured using ELISA and steady-state model evaluation. Vaspin intervention significantly reduced FBG, FINS, and HOMA-IR levels in the GDM group, while L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, blocked these effects. INS-1 cells were used to establish a high-glucose model, and laser confocal microscopy, ELISA, and Griess reagent were employed to detect reactive oxygen species (ROS), eNOS, and nitric oxide (NO) levels. Exogenous Vaspin administration improved ROS, eNOS, and NO levels, but these effects were inhibited by L-NAME. Collectively, these results propose a model in which the protective effect of Vaspin against insulin resistance in GDM may be mediated, at least in part, through the ROS/eNOS/NO pathway.

Iron overload is harmful to health and associates with intracellular excessive reactive oxygen species (ROS) generation. Nobiletin (Nob) is known to be antioxidant and anti-inflammatory. However, whether Nob can protect endothelial cells against iron overload has not been studied, and the specific mechanism has not yet been elucidated. In this study, we have identified the protective effects of Nob, and its underlying molecular mechanism in human umbilical vein endothelial cells (HUVECs) suffered from iron overload via ROS/ADMA/DDAHII/eNOS/NO pathway. We found that compared with 50 μM iron dextran treatment, co-treatment with 20 μM Nob increased cell viability and decreased lactate dehydrogenase activity. Besides, Nob could upregulate DDAHII expression and activity, promote eNOS phosphorylation to produce more NO, reduce ADMA content, and therefore increase superoxide dismutase, catalase, and glutathione peroxidase activities, and decrease malondialdehyde level and ROS generation. Nob also inhibited mitochondrial permeability transition pore (mPTP) openness and cleaved caspase-3 expression, and decreased apoptosis induced by iron overload. These results were consistent when Nob was replaced by the positive control reagents L-arginine (a competitive substrate of ADMA), cyclosporin A (an mPTP closing agent), or edaravone (a free radical scavenger). The addition of pAD/DDAHII-shRNA adenovirus reversed the above effects of Nob. These data suggested that the protective mechanism of Nob was to inhibit ROS burst, upregulate DDAHII expression and activity, promote eNOS phosphorylation, produce NO, reduce ADMA content, and ultimately alleviate iron overload damage in vascular endothelium.