Sustained exercise-induced elevations in shear rate (SR) have been well established as beneficial for improving endothelial function. However, the impact of intermittent fluctuations in SR is not understood. We investigated the effect of intermittent SR elevations compared with sustained elevations on peripheral endothelial function. Brachial artery flow-mediated dilation (FMD) was assessed in 13 adults (9 M/4 F; 22 ± 4 yr) before and after 30 min of handgrip exercise. Three different rhythmic forearm exercise interventions were performed at a rate of 20 contractions/min. Intermittent exercises (6 × 3 min exercise interspersed by 2 min of rest) were performed at 25% (INT-25%) and 15% (INT-15%) maximum voluntary contraction (MVC), and continuous exercise was completed at 15% MVC. Brachial artery diameter and velocity were measured using Doppler ultrasound. The total increase in SR above baseline throughout exercise was greater during INT-25% (4,441 ± 516 s^-1) and continuous (4,070 ± 407 s^-1) compared with INT-15% (2,811 ± 342 s^-1, P < 0.05). The %FMD increased following all exercises (INT-25%: 5.7 ± 1.2% to 8.1 ± 1.2%; INT-15%: 5.2 ± 1.2% to 7.0 ± 1.1%; continuous: 5.5 ± 1.3% to 6.8 ± 1.3%, P < 0.05 for all). The increase following INT-25% was significantly greater than INT-15% and continuous (P < 0.05 for both). Normalized FMD to shear rate area under the curve increased with intermittent exercise (INT-25%: 2.2 ± 0.2% to 3.4 ± 0.3%; INT-15%: 2.1 ± 0.2% to 3.2 ± 0.2%, P < 0.05 for both) but did not following continuous (2.1 ± 0.2% to 2.5 ± 0.1%, P = 0.06). The increase in normalized FMD with intermittent exercises were greater than continuous (P < 0.05 for both). These findings suggest intermittent fluctuations in SR during handgrip exercise may be more beneficial than sustained elevations on improving peripheral endothelial function.NEW & NOTEWORTHY Exercise-induced increases in shear rate is a well-established stimulus for improving peripheral endothelial function. This study presents novel findings that intermittent elevations in shear rate may be more effective at acutely improving endothelial function compared with continuous elevations. Despite similar increases in total shear rate during handgrip exercise intermittent elevations produced a significantly greater increase in endothelial function when compared with continuous elevations potentially indicating intermittent elevations as a more effective stimulus for acute improvements.

2013-03-01·Anti-cancer agents in medicinal chemistry4区 · 医学

Inhibiting the Interaction of cMET and IGF-1R with FAK Effectively Reduces Growth of Pancreatic Cancer Cells in vitro and in vivo

4区 · 医学

Article

作者: Magis, Andrew T. ; He, Di-Hua ; Hochwald, Steven N. ; Sebti, Said M. ; Kurenova, Elena ; Lawrence, Nicholas J. ; Zhang, Jianliang ; Zajac-Kaye, Maria ; Ucar, Deniz A.

Pancreatic cancer is one of the most lethal diseases with no effective treatment. Previously, we have shown that FAK is overexpressed in pancreatic cancer and plays a key role in cancer cell survival and proliferation. FAK has been shown to interact with growth factor receptors including cMET and IGF-1R. As a novel therapeutic approach, we targeted the protein interaction of FAK with growth factor receptors to block tumor growth, alter signaling pathways and sensitize cells to chemotherapy. We have selected a small molecule compound (INT2-31) that decreases phosphorylation of AKT via disrupting interaction of FAK with cMET and IGF-1R. Our results demonstrate that interaction of a small molecule compound with FAK decreases phosphorylation of FAK Y397 while increasing FAK Y407 phosphorylation, without inhibiting the kinase activity of FAK and dramatically reduces downstream signaling to AKT. Our lead compound, INT2-31, demonstrates significant inhibition of tumor cell growth in two orthotopic models of pancreatic cancer. In addition, INT2-31 increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer growth.

2011-09-01·Anti-cancer agents in medicinal chemistry4区 · 医学

A Novel Small Molecule Inhibitor of FAK and IGF-1R Protein Interactions Decreases Growth of Human Esophageal Carcinoma

4区 · 医学

Article

作者: He, Di-Hua ; Hochwald, Steven N. ; Ostrov, David A. ; Kurenova, Elena ; Cox, Audrey ; Ucar, Deniz A.

INTRODUCTION:

Esophageal cancer remains an aggressive disease with poor survival rates. FAK and IGF-1R are two important tyrosine kinases important for cell survival signaling and found to be upregulated in esophageal cancer. Our hypothesis is that a novel small molecule compound that disrupts FAK and IGF-1R protein-protein interactions (PPIs) would decrease the growth of human esophageal cancer.

METHODS:

The compound INT2-31 (NSC344553) was identified from a virtual high throughput screen to bind to FAK and disrupt PPIs. The in vitro effects of this compound, +/- 5-FU chemotherapy, on cell signaling, viability and apoptosis in human esophageal cancer cells (KYSE 70, 140) and a direct esophageal cancer xenograft was evaluated.

RESULTS:

INT2-31 caused a disruption of PPIs between FAK and IGF-1R starting at a concentration of 1μM. It also caused a dose dependent inhibition of cell viability and induction of apoptosis at low micromolar doses. These effects were associated with decreased AKT and ERK1/ERK2 phosphorylation. INT2-31 treatment, when administered via IP injection, at 50mg/kg, resulted in an in vivo decrease in tumor growth in a direct xenograft. Furthermore, treatment with 5-FU chemotherapy combined with INT2-31 resulted in a synergistic increase in apoptosis and decrease in tumor growth compared to 5-FU or INT2-31 alone.

CONCLUSIONS:

A novel compound that disrupts the PPIs of FAK and IGF-1R results in decreased tumor proliferation and increased apoptosis. These effects appear to be mediated through downregulation of p-AKT and p-ERK. This compound deserves further study as a novel treatment strategy in patients with esophageal cancer.

100 项与 INT-231 相关的药物交易

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