Transcriptional factor nuclear factor-kappaB (NF-κB) plays a crucial role in human breast cancer cell invasion and metastasis. The carboxyl terminus of Hsc70-interacting protein (CHIP) is a U-box-type ubiquitin ligase that induces ubiquitination and proteasomal degradation of its substrate proteins. In this study, we investigated the role of CHIP in the NF-κB pathway in the invasion of MDA-MB-231 cells, a highly aggressive breast cancer cell line. We showed that overexpression of CHIP significantly inhibits the invasion of the MDA-MB-231 cells. The overexpression of CHIP suppressed expression of urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in MDA-MB-231 cells. Moreover, CHIP strongly inhibited the nuclear localization and the transcriptional activity of NF-κB. The activation of the IkappaB kinase complex (IKK) was also blocked by CHIP overexpression. Importantly, CHIP overexpression resulted in a significant decrease in the level of TNF receptor-associated factor 2 (TRAF2), an upstream key player in the NF-κB pathway. However, the level of TRAF2 was restored after treatment with a proteasome inhibitor, MG-132. Moreover, CHIP overexpression promoted the ubiquitination of TRAF2. We also found cell invasion significantly decreased in cells transfected with TRAF2 small interfering RNA (siRNA). In contrast, when CHIP expression was suppressed by siRNA in poorly invasive MCF-7 cells, cell invasion significantly increased in conjunction with enhanced NF-κB activation and TRAF2 levels. Taken together, these results suggest that CHIP regulates NF-κB-mediated cell invasion via the down-regulation of TRAF2.

Far-infrared radiation (FIR) has been shown to exert positive effects on the cardiovascular system. However, the biological effects of FIR on bone marrow-derived stem cells (BMSCs) are not understood. In the present study, BMSCs were isolated from rat femur bone marrow and cultured in vitro. To investigate the effects of an FIR generator with an energy flux of 0.13 mW/cm2 on rat BMSCs, survival of BMSCs was measured by crystal violet staining, and cell proliferation was additionally measured using Ez-Cytox cell viability, EdU, and Brd U assays. FIR preconditioning was found to significantly increase BMSC proliferation and survival against H2O2. The scratch and transwell migration assays showed that FIR preconditioning resulted in an increase in BMSC migration. qRT-PCR and Western blot analyses demonstrated that FIR upregulated Nanog, Sox2, c-Kit, Nkx2.5, and CXCR4 at both the mRNA and protein levels. Consistent with these observations, PD98059 (an ERK inhibitor) and AMD3100 (a CXCR4 inhibitor) prevented the activation of CXCR4/ERK and blocked the cell proliferation and migration induced by FIR. Overall, these findings provide the first evidence that FIR confers a real and significant benefit on the preconditioning of BMSCs, and might lead to novel strategies for improving BMSC therapy for cardiac ischemia.

A ging is a physiological process associated with an increase in cardiovascular morbidity and mortality even in the absence of known cardiovascular risk factors. 1 The main feature of arterial aging is the thickening, dilation, and stiffening of the artery, 2,3 which is described as senile arteriosclerosis. 4 The repeated cycles of distension and elastic recoil of the arterial wall accelerate the fragmentation and depletion of elastin, leading to a substantial increase in the inner diameter and the deposition of collagen with increasing stiffness.5 As a result, the stiffening of the proximal aorta and early wave reflection give rise to the development of isolated systolic hypertension, left ventricular hypertrophy, and heart failure with a basis on a ventricular-vascular coupling mechanism; all of these factors lead to an increase of cardiovascular mortality with aging. 5,6 Thus, the assessment of mechanical properties of the artery in humans using noninvasive techniques is of growing importance. For quantification of aortic elastic properties, there are many noninvasive measures, including pulse wave velocity and echocardiographic techniques presented as distensibility, strain, and pressure-strain elastic moduli.7-11 However, these methods represent a global estimation of arterial elasticity and, therefore, have limitations because arterial changes usually begin as regional changes. With the availability of more advanced ultrasound techniques, a novel automated speckletracking method using velocity-vector imaging (VVI) software has facilitated the assessment for angle-independent and instantaneous quantification of arterial elastic properties by providing the 2-dimensional-derived tissue radial velocity (RV), circumferential strain, and strain rate in both regional and segmental aspects. 12-15We previously showed that arterial assessment using VVI represents a new method for quantifying vascular alteration not only in the clinical conditions of vasculitis 12,13 but also in other disorders associated with aging.16 Despite these investigations, further histological validation will facilitate the clinical application of VVI. Therefore, the purpose of this study was to compare the parameters of VVI between young and senescent dogs and to assess the correlations between the VVI parameters and histological changes. Objective-Velocity-vector imaging (VVI) represents a valuable new method for noninvasive quantification of vascular properties associated with aging. The purpose of this study was to assess the correlations between VVI parameters and histological changes with aging. Approach and Results-Fourteen mongrel dogs were classified as either young (n=7; age, 1-2 years; female; weighing 22-29 kg) or senescent (n=7; age, 8-12 years; female; weighing 36-45 kg). The short-axis image of the descending thoracic aorta was obtained for VVI analysis with transesophageal echocardiography. The location of the image was identified using fluoroscopic guidance, and the aortic tissue was extracted. After dividing the aortic wa...

Gene transfer of basic fibroblast growth factor (bFGF) has been shown to induce significant endothelial migration and angiogenesis in ischemic disease models.

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ObjectiveAlthough dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes.MethodsEight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation.ResultsGemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis.ConclusionGemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes.

BackgroundThe cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO).Methods and Results9 week old Apo E KO mice were infused subcutaneously with AngII (1 µg/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 µg, 1 µg, to 2 µg/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 µg, 1 µg, and 2 µg of sRAGE in AngII group resulted in the dose-dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells.ConclusionThe results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII-induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation.