BACKGROUND Low levels of p27Kip1 are associated with high aggressiveness and poor prognosis in various malignancies, including colorectal carcinoma. The authors showed that S phase kinase protein 2 (Skp2), the specific ubiquitin ligase subunit that targets p27Kip1 for degradation, was overexpressed and was inversely related to p27Kip1 levels in patients with colorectal carcinoma. The essential role of cyclin kinase subunit 1 (Cks1) in Skp2‐dependent p27 degradation was recently discovered, but its role in human malignancies is unknown. METHODS Quick‐frozen colorectal tumor samples from 30 patients were separated by electrophoresis on sodium dodecyl sulfate–polyacrylamide gels, transferred to nitrocellulose, and probed with highly specific monoclonal antibodies directed against Cks1, Skp2, and p27Kip1. The expression of Cks1 was also examined by immunohistochemistry using formalin‐fixed, paraffin‐embedded tissue sections from the same patients. RESULTS A strong correlation was found between Cks1 levels and Skp2 expression and loss of tumor differentiation. A significant inverse relation was also observed between levels of Cks1 and p27Kip1 and overall survival. CONCLUSIONS The results of the current study suggest that increased expression of Cks1 may have an important causative role in decreasing levels of p27 in patients with aggressive colorectal carcinoma. Cancer 2004. © 2004 American Cancer Society.
Decreased renal perfusion and function are induced by IAP pressure of 14 mmHg. These adverse effects are probably related to interference with the NO system, and could be partially ameliorated by pretreatment with NTG.
Acute kidney injury (AKI) is a common clinical problem that still lacks effective treatment. Phosphodiesterase-5 (PDE5) inhibitors possess anti-apoptotic and anti-oxidant properties, making it a promising therapy for ischemia-reperfusion (I/R) injury of various organs. The present study evaluated the early nephroprotective effects of Tadalafil, a PDE5 inhibitor, in an experimental model of renal I/R. Sprague-Dawley rats were divided into two groups: vehicle-treated I/R (n = 10), and Tadalafil (10 mg/kg po)-treated I/R group (n = 11). After removal of the right kidney and collection of two baseline urine samples, the left renal artery was clamped for 45 min followed by reperfusion for 60, 120, 180, and 240 min. Functional and histological parameters of the kidneys from the various groups were determined. In the vehicle-treated I/R group, glomerular filtration rate was significantly reduced compared with that in normal kidneys. In addition, the ischemic kidney showed remarkable cast formation, necrosis, and congestion, a consistent pattern of acute tubular necrosis. Furthermore, urinary excretion of NGAL and KIM-1, two novel biomarkers of kidney injury, substantially increased following I/R insult. In contrast, Tadalafil treatment resulted in a significant improvement in kidney function and amelioration of the adverse histological alterations of the ischemic kidney. Noteworthy, the urinary excretion of NGAL and KIM-1 markedly decreased in the Tadalafil-treated I/R group. These findings demonstrate that Tadalafil possesses early nephroprotective effects in rat kidneys subjected to I/R insult. This approach may suggest a prophylactic therapy for patients with ischemic AKI.
The mechanism underlying this phenomenon is largely unknown. This study was designed to investigate the involvement of endothelin (ET)-1 and nitric oxide (NO) systems in IAP-induced renal dysfunction. Rats were subjected to IAP of 14 mmHg for 1 h, followed by a deflation for 60 min (recovery). Four additional groups were pretreated with 1) ABT-627, an ET A antagonist; 2) A-192621, an ETB antagonist; 3) nitroglycerine; and 4) N G -nitro-L-arginine methyl ester, a NO synthase inhibitor, before IAP. Urine flow rate (V), absolute Na ϩ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. Significant reductions in kidney function and hemodynamics were observed when IAP was applied. V decreased from 8.1 Ϯ 1.0 to 5.8 Ϯ 0.5 l/min, UNaV from 1.08 Ϯ 0.31 to 0.43 Ϯ 0.10 eq/min, GFR from 1.84 Ϯ 0.12 to 1.05 Ϯ 0.06 ml/min (Ϫ46.9 Ϯ 2.7% from baseline), and RPF from 8.62 Ϯ 0.87 to 3.82 Ϯ 0.16 ml/min (Ϫ54 Ϯ 3.5% from baseline). When the animals were pretreated with either ABT-627 or A-192621, given alone or combined, the adverse effects of IAP on GFR, RPF, V, and UNaV were significantly augmented. When the animals were pretreated with nitroglycerine, the adverse effects of pneumoperitoneum on GFR and RPF were substantially improved. In contrast, pretreatment with N G -nitro-L-arginine methyl ester remarkably aggravated pneumoperitoneum-induced renal dysfunction. In conclusion, decreased renal excretory function and hypofiltration are induced by increased IAP. These effects are related to impairment of renal hemodynamics and could be partially ameliorated by pretreatment with nitroglycerine and aggravated by NO and ET blockade.rat; intra-abdominal pressure PNEUMOPERITONEUM AT PRESSURE above 10 mmHg during laparoscopic surgery has been shown to produce transient oliguria and reduced glomerular filtration rate (GFR) and renal blood flow (RBF) (3,9,16,33,34). Despite much research in this field, the systemic physiological consequences of CO 2 pneumoperitoneum and the mechanisms underlying its adverse effects on renal hemodynamics and excretory function are not fully understood (9). However, there is compelling experimental evidence that the adverse renal effects induced by pneumoperitoneum are affected by the level of intra-abdominal pressure (IAP), volume status, degree of hypercarbia, positioning, and individual hemodynamic and renal reserves (9, 10). Additional factors that may affect renal function during pneumoperitoneum include direct compression of the renal parenchyma and renal vein (4, 17), increased resistance in the renal vasculature (47), and release of vasoconstrictors, such as vasopressin, angiotensin II, catecholamines, and endothelin (ET)-1 (1, 13). The latter is a very potent natural mammalian vasoconstrictor agent (25), acting on the cardiovascular and renal systems and other target organs by binding to two major types of receptors, ET A and ET B (2,25,36). High abundance of ET A receptors has been detected in the aorta, heart, and kidney, whereas ET B receptors are expre...
Renal injury severity after nephron sparing surgery could be quantitatively assessed by measuring urinary NGAL and KIM-1.
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