Bisphosphonates are potent bone resorption inhibitors, among which alendronate sodium (ALN) is commonly prescribed for most osteoporosis patients, but long-term application of ALN can cause bisphosphonate-related osteonecrosis of jaw (BRONJ), the pathogenesis of which remains unclear. Previous studies have suggested that bisphosphonates cause jaw ischemia by affecting the biological behavior of vascular endothelial cells, leading to BRONJ. However, the impacts of ALN on vascular endothelial cells and its mechanism remain unclear. The purpose of this work is to assess the influence of ALN on human umbilical vein endothelial cells (HUVECs) and clarify the molecular pathways involved. We found that high concentration of ALN induced G1 phase arrest in HUVECs, demonstrated by downregulation of Cyclin D1 and Cyclin D3. Moreover, high concentration of ALN treatment showed pro-apoptotic effect on HUVECs, demonstrated by increased levels of the cleaved caspase-3, the cleaved PARP and Bax, along with decreased levels of anti-apoptotic protein Bcl-2. Further experiments showed that ERK1/2 phosphorylation was decreased. Additionally, ALN provoked the build-up of reactive oxygen species (ROS) in HUVECs, leading to ERK1/2 pathway suppression. N-acetyl-L-cysteine (NAC), a ROS scavenger, efficiently promoted the ERK1/2 phosphorylation and mitigated the G1 phase arrest and apoptosis triggered by ALN in HUVECs. PD0325901, an inhibitor of ERK1/2 that diminishes the ERK1/2 phosphorylation enhanced the ALN-induced G1 phase arrest and apoptosis in HUVECs. These findings show that ALN induces G1 phase arrest and apoptosis through ROS-mediated ERK1/2 pathway inhibition in HUVECs, providing novel insights into the pathogenic process, prevention and treatment of BRONJ in individuals receiving extended use of ALN.

Background: Hyperhomocysteinemia is a risk factor for contrast-induced nephropathy. Folic acid can attenuate such nephropathies in rats. The protective effect of folic acid against contrast-induced nephropathy has not been studied in humans. We aimed to investigate the effect of folic acid on the incidence of contrast-induced nephropathy (CIN) after coronary catheterization in patients with hyperhomocysteinemia.Methods: This was a single-center, prospective, double-blind, randomized controlled trial (ClinicalTrials.gov, NCT02444013). In total, 412 patients (mean age: 65 ± 12 years, 268 male) with plasma homocysteine ≥15 μM, who underwent coronary arteriography (CAG) or percutaneous coronary intervention (PCI) from May 2015 to August 2018, were enrolled. Patients were randomly assigned to two groups: a treatment group (n = 203), taking 5 mg of folic acid (orally, three times/day) immediately after enrollment and for 72 h after operation, and a control group (n = 209), taking placebo. Contrast-induced nephropathy was defined as an increase in serum creatinine of >25% or 44 μM within 48 or 72 h after contrast medium administration.Results: In total, 50 (12%) patients developed CIN after 48 h after catheterization, including 16 (8%) in the treatment group and 34 (16%) in the control group (P = 0.009). Meanwhile, 53 (13%) patients developed CIN after 72 h of CAG/PCI, including 18 (9%) in the treatment group and 35 (17%) in the control group (P = 0.017). The incidence of contrast-induced nephropathy in the treatment group was lower than that in the control group (P = 0.017). Logistic regression analysis confirmed that administration of folic acid was a protective factor against contrast-induced nephropathy (RD = 0.0788, 95%CI: 0.0105–0.1469, P = 0.019). We found no serious adverse events associated with folic acid. No death or hemodialysis occurred in either group.Conclusions: Perioperative administration of folic acid attenuates the incidence of contrast-induced nephropathy after coronary catheterization in patients with hyperhomocysteinemia.Clinical Trial Registration:ClinicalTrials.gov, identifier [NCT02444013].

Background. Glycemic instability confers a risk of poor prognosis in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate whether HbA1c variability provided additional value over mean HbA1c for predicting subclinical left ventricular remodeling and dysfunction in T2DM patients. Methods: A total of 466 T2DM patients with normal cardiac structure and function were recruited and prospectively followed up for a median of 4.7 y. HbA1c was measured quarterly. The intrapersonal mean and standard deviation (SD) of HbA1c measurements were calculated, and SD-HbA1c was considered as a measure of HbA1c variability. All participants underwent transthoracic echocardiography at baseline and after follow-up. Results: In multivariable regression analyses, SD-HbA1c was independently associated with annualized changes in left ventricular end diastolic diameter, interventricular septum, left ventricular posterior wall, left ventricular mass index, left ventricular ejection fraction, E/e' ratio, and E/A ratio (P < 0.001). Subgroup analysis based on mean HbA1c levels (< 7.0%, 7.0-7.5%, and >= 7.5%) further confirmed that SD-HbA1c was associated with most of the above parameters regardless of mean HbA1c levels. Conclusion: This study indicates that HbA1c variability adds to the mean value in predicting subclinical left ventricular remodeling and dysfunction in T2DM patients.

Senescence is an independent risk factor for the development of cardiovascular disorders. A number of studies have suggested that oxidative stress is the primary cause of endothelial cell senescence which is the basic of endothelial aging. The goal of the present study was to investigate the role and the underlying mechanisms of NO in regulating endothelial cell senescence. Endothelial senescence was judged by senescence-associated beta-galactosidase assay (SA-beta-gal) and PAI-1 protein expression. The senescence of human umbilical vascular endothelial cells (HUVECs) was induced by H2O2. NO donor SNP could effectively decrease the generation of intracellular reactive oxygen species (ROS), SA-beta-gal activity, and PAI-1 protein level. Mechanistically, biotin switch assay and western blot revealed NO donor increased cytoplasm and nuclear p65 S-nitrosylation, and decreased cytoplasm and nuclear NF-kappa B p65 protein level. Furthermore, the effects of pcDNA-eNOS on senescence cells revealed that NO mediated cell senescence through S-nitrosylation of NF-kappa B, and inhibited NF-kappa B p65 related inflammatory signaling pathway and production of reactive oxygen, which may contribute to the endothelial dysfunction.

To study the mechanism of the transforming growth factor-β(TGF-β) in Ginsenoside Rb1 against the replicative senescence of human umbilical vein endothelial cells (HUVECs). Replicative Senescence model was established by serial subcultivation of primary HUVECs in vitro. Then, Cells were divided