Synergistic roles of p53 and HIF1α in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways.

INTRODUCTION: mTOR and MDM2 signaling pathways are frequently deregulated in cancer development, and inhibition of mTOR or MDM2 independently enhances carcinoma-cell apoptosis. However, responses to mTOR and MDM2 antagonists in renal cell carcinoma (RCC) remain unknown. MATERIALS AND METHODS: A498 cells treated with MDM2 antagonist MI-319 and/or mTOR inhibitor rapamycin were employed in the present study. Cell apoptosis and Western blot analysis were performed. RESULTS AND CONCLUSION: We found that the MDM2 inhibitor MI-319 induced RCC cell apoptosis mainly dependent on p53 overexpression, while the mTOR antagonist rapamycin promoted RCC cell apoptosis primarily through upregulation of HIF1α expression. Importantly, strong synergistic effects of MI-319 and rapamycin combinations at relatively low concentrations on RCC cell apoptosis were observed. Depletion of p53 or HIF1α impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1α remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1α are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1α may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy.

[Influence of the interruption of arteria iliaca interna distal end on penile vascularity and erectile function in male renal transplant recipients].

OBJECTIVE: It is controversial whether unilateral interruption of the arteria iliaca interna distal end affects penile hemodynamics and erectile function. The purpose of this study was to prospectively evaluate this influence by detecting the blood flow of the penile artery before and after renal transplantation. METHODS: Thirty-three patients with chronic renal failure (CRF) on maintenance hemodialysis (MHD) received renal transplantation, the grafts revascularized by end-to-end anastomosis to the right internal iliac artery. Six months before and after the surgery, we obtained the IIEF scores of the patients, recorded their penile blood flow on color Doppler ultrasonography and the levels of serum creatinine, hemoglobin and serum cholesterol, and analyzed post-transplantation immunosuppressive medication. RESULTS: The patients ranged in age from 21 to 55 years, of whom 36% had erectile dysfunction (ED) during MHD, and 33% after renal transplantation. A total of 67% of the renal transplant recipients (RTR) complained of unchanged and 15% deteriorated ED, while 18% admitted improved erectile function. The patients showed a significantly stronger sexual desire after the transplantation than before it (6.2 +/- 1.6 vs 8.9 +/- 0.9, P < 0.01). There was a significant decrease in peak systolic velocity (PSV) in the cavernous arteries after transplantation as compared with pre-transplantation (P < 0.01). Penile arterial blood flow insufficiency was found in none of the RTRs. CONCLUSION: Unilateral interruption of the internal iliac artery decreases penile arterial blood flow, but not to such a degree as to result in ED. Unilateral interruption of the arteria iliaca interna distal end does not affect the erectile function of RTRs.

[Living related donor kidney transplantation: analysis of 117 cases].

OBJECTIVE: To summarize the clinical experience in living related donor kidney transplantation. METHODS: 117 patients with different nephropathies underwent transplantation of kidneys donated by their collateral relative in three generations. All donor kidneys were removed by open nephrectomy. Immunosuppressive protocols which consisting of cyclosporine A/tacrolimus, mycophenolate mofetil/azathioprine/rapamycin, and steroid were used in all patients as immunosuppressors. Follow-up was conducted for 1-44 months. RESULTS: Delayed graft function recovery occurred in 2 patients. Acute rejection episodes occurred in 18 patients, and the condition was reversed by high intravenous dose of methyl-prednisolone or polyclonal anti-T-cell antibodies. Follow-up showed that all the patients survived with normal kidney function, and the donors kept good kidney function with normal life quality. Hypertension was found in 2 donors and diabetes mellitus was found in 1 donor. CONCLUSION: Careful evaluation of both psychological and physical status of the donors and optimal physical status of recipients before operation are critical for successful kidney transplantation. Injury of graft kidney should be reduced and recipients should be treated with sufficient immunosuppressive regimen in early stage after transplantation.

Prevalence and influential factors of erectile dysfunction in male renal transplant recipients: a multiple center survey.

BACKGROUND: Renal transplants can improve the quality of life for recipients, but the quality of their sexual life might not be improved. This study was conducted to research the prevalence of erectile dysfunction (ED) and the influential factors in male renal transplant recipients (RTRs). METHODS: A cross-sectional survey was conducted in three renal transplantation centers. Structured questionnaires were administrated by trained interviewers to 824 male renal transplant patients, who had active sexual lives in the last 6 months. RESULTS: Complaints of ED were reported by 75.5% of the 809 RTRs (age range 19 - 75 years, mean age (45 +/- 10) years), whose questionnaires were completed. Mild, moderate and severe ED were reported at 53.6%, 8.3% and 13.6%, respectively. The mean age and the graft duration were significantly higher in male RTRs with ED compared to potent graft recipients (P = 0.00 and 0.04, respectively). The prevalence of ED increased with the increase in age. It was 60.7%, 65.8%, 75.2%, 87.5% and 92.2% in patients with age below 30 years, 31 - 40 years, 41 - 50 years, 51 - 60 years and over 60 years, respectively (P = 0.000). Moreover, the severity of ED increased with aging. The percentage of moderate and severe cases of ED increased from 6.7% in patients below 40 years to 28.9% in those over 40 years (P = 0.000). The prevalence of ED in the RTR who had no occupation was higher than in those who were holding a position (P = 0.001). The prevalence of ED decreased with the increase in the education level. The prevalence of ED was 94.3%, 86.4%, 74.0% and 67.8% in men with elementary school or lower, middle school, high school, and college or higher degrees, respectively (P = 0.000). Patients, whose distal end of arteria iliaca interna was interrupted and underwent iterative transplantation, worried transplanted kidney function was impacted by sexual life, and received cyclosporine (CsA)-based immunosuppressive regimens, were more likely to have ED (P = 0.000, 0.001, 0.000, 0.000, respectively). After Logistic regression analysis, only five factors, age, education level, interruption of arteria iliaca interna distal end, worrying transplanted kidney function impacted by sexual life and CsA-based immunosuppressive regimens sustained their significance. CONCLUSIONS: Renal transplant has varying effects on erectile function. ED is highly prevalent among RTRs and its influential factors are multiple. Age, education level, interruption of arteria iliaca interna distal end, worrying transplanted kidney function impacted by sexual life, CsA-based immunosuppressive regimens are the main influential factors of ED in male RTRs.

[Influential factors and therapeutic options for erectile dysfunction in allograft renal transplantation recipients].

The quality of sexual life is important for renal transplantation recipients. With the increase of survival rate of renal transplantation, the quality of the male recipients' sexual life, especially their erectile function, has been generally remarked. The prevalence of ED is 35.8%-78.3% in male allograft renal transplantation recipients. And it can be caused by various factors, such as age, dialysis time, modus operandi, hemoglobin level, deprementia, immunosuppressant, and diabetes. We give an overview of the therapeutic options for ED in this special population. Sildenafil is effective and safe. If the oral drug fails, we can choose intracavernosal injection and penile prosthesis implantation. Nevertheless, three-piece prostheses should be avoided.

A clinical intervention study among 463 essential hypertensive patients with metabolic syndrome / 中华心血管病杂志

<p><b>OBJECTIVE</b>To study the role of baseline risk factors in predicting the onset of diabetes among essential hypertensive patients with metabolic syndrome (MS) and to evaluate an ideal therapeutic regime that could reduce the risk factors and risk of onset of diabetes.</p><p><b>METHODS</b>A randomized parallel clinical trial in essential hypertensive patients of grade 1 or 2 was conducted. Two of the three components (1) increased waist circumference and/or BMI; (2) increased triglycerides (TG) and/or decreased high-density lipoprotein cholesterol; (3) impaired glucose tolerance (IGT) were present define the MS. The three intervention therapy groups were: indapamide + fosinopril (I + F, n = 151); atenolol + nitrendipine (A + N, n = 160); atenolol + nitrendipine + metformin (A + N + M, n = 152). Each case was followed-up monthly and the dosage of medicine taken be adjusted according to their BP level. The plasma glucose during fasting and two hours after taking 75 g glucose orally was also measured every six months. The new onset of diabetes was diagnosed according to the criteria. OGTT, insulin release test, lipid analysis, body weight and waist circumference were measured again at the last follow-up.</p><p><b>RESULTS</b>(1) The lowering of BP was similar among the three groups (P > 0.05). 23 new diabetes onsets occurred, being 10 in group I + F and 8 in group A + N and 5 in group A + N + M, respectively (P > 0.05); (2) Proportions of patients' risk factors decreased significantly in group A + N or A + N + M, e.g. the proportions of high TG in each group reduced by 14.7% and 9.3% respectively (P < 0.05), the central fat distribution reduced by 16.7% and 15.9% respectively (P < 0.05) and the IGT reduced by 6.6% and 29.6% respectively (P < 0.05). However no changes were found in group I + F; (3) After 1 year and 5 months' follow-up, the proportions of main risk factors (high TG, central fat distribution and IGT) in the three groups were 91%, 96%, 83% and 90%, 88%, 47%, respectively. The difference of IGT was significant between two groups (P < 0.01) and the proportions of having three risk factors were 70% and 31% in the two groups (P < 0.01); (4) I + F group was better than A + N group in reduction of TG and central fat distribution. And A + N + M group improved in all risk factors.</p><p><b>CONCLUSIONS</b>IGT alone or combined with increased TG plus abdominal obesity are the most important risk factors in predicting a new onset of diabetes among essential hypertensive patients with MS. Metformin in combination with atenolol plus nitrendipine can significantly prevent the onset of diabetes as well as improve patients' metabolic abnormality.</p>