Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia

PURPOSE It has been proposed that a deficiency in the axonal transport of nerve growth factor (NGF) may have an important role in inducing diabetic neuropathy, which contributes to diabetic cystopathy. Therefore, in streptozotocin (Sigma Chemical Co., St. Louis, Missouri) induced diabetic rats we investigated the relationship of bladder function with NGF levels in the bladder and lumbosacral dorsal root ganglia, which contain afferent neurons innervating the bladder.MATERIALS AND METHODS At 6 and 12 weeks after the induction of diabetes with streptozotocin (65 mg./kg. intraperitoneally) the effects of diabetes on Adelta afferent fiber dependent, conscious voiding were evaluated by metabolic cage measurements and awake cystometry. The effects of diabetes on C-fiber mediated bladder nociceptive responses were also investigated by cystometry with intravesical instillation of 0.25% acetic acid in the rats under urethane anesthesia. NGF levels in the bladder and L6 to S1 dorsal root ganglia were measured by enzyme-linked immunosorbent assay 3, 6, 9 and 12 weeks after streptozotocin injection.RESULTS In diabetic rats NGF levels in the bladder and L6 to S1 dorsal root ganglia were significantly decreased 12 weeks after streptozotocin injection (p <0.01). In cystometry and metabolic cage studies bladder capacity and post-void residual volume were significantly increased 12 weeks after streptozotocin injection (p <0.01). Bladder nociceptive responses revealed by a reduction in inter-contraction intervals after acetic acid infusion were significantly decreased in a time dependent manner 12 weeks after streptozotocin injection.CONCLUSIONS Rats with streptozotocin induced diabetes mellitus showed a significant time dependent decrease in NGF levels in the bladder and L6 to S1 dorsal root ganglia that was associated with voiding dysfunction attributable to defects in Adelta and C-fiber bladder afferents. Therefore, reduced production of NGF in the bladder and/or impaired transport of NGF to L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, may be an important mechanism inducing diabetic cystopathy.     

Association between renal dysfunction and mortality among inhabitants in the region around the Jinzu River basin polluted by cadmium

A follow-up study was conducted on 5725 inhabitants (men 2858, women 2867) in and around the Jinzu River basin to determine the influence of environmental Cd exposure on mortality. In the Jinzu River basin, standardized mortality ratios (SMRs) investigated according to urinary findings (protein, glucose, and protein+glucose) were significantly low in the urinary protein-, glucose-, and protein+glucose-negative groups. SMRs calculated after dividing urinary protein- and glucose-positive status into two levels were lowest in the proteinuria- and glycosuria-negative groups and tended to be high in the higher positive groups. In the Jinzu River basin, Cox's hazard ratios were significantly higher for men and women in the urinary protein, glucose and protein+glucose-positive-groups. In the same analysis where the urinary protein- and glucose-positive subjects were divided into two levels, mortality was demonstrated to be higher in the groups with the greater degrees of proteinuria and glycosuria. In the Jinzu River water system almost all SMRs and Cox's hazard ratios showed statistical significance. This was not the case in the other water systems. Mortality of inhabitants with Cd-induced renal injury is increased in the Jinzu River basin.     

Tandem high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation for recurrent soft tissue sarcoma

BACKGROUND: Patients with recurrent soft tissue sarcoma (STS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDC) with hematopoietic stem cell support in this disease has not been established. CASE REPORT: We report on two patients with recurrent STS who were treated with tandem HDC supported by autologous peripheral blood stem cell transplantation (PBSCT). One patient with malignant fibrous histiocytoma recurred with multiple lung metastases. This patient achieved a partial response after two cycles of induction chemotherapy consisting of ifosfamide and epirubicin. During four cycles of induction chemotherapy, peripheral blood stem cells (PBSCs) were harvested. Tandem high-dose ICE regimen (ifosfamide 3 g/m2 on days-7 to -3, carboplatin 400 mg/m2 on days-7, -5 and 3, etoposide 500 mg/m2 on days-7, -5 and 3) supported by autologous PBSCT gave rise to further regression of the tumors. Another patient with malignant hemangiopericytoma was treated by tandem high-dose ICE regimen supported by autologous PBSCT after the 3rd removal of abdominal tumors. Relapse-free intervals until the 1st, 2nd and 3rd relapses were 40, 19 and 22 months, respectively. Tandem high-dose ICE regimen might delay the relapse. CONCLUSION: These observations suggest that a tandem high-dose ICE regimen with autologous PBSCT is feasible with some clinical efficacy in the control of refractory STS.     

Analysis of cell growth inhibitory effects of catechin through MAPK in human breast cancer cell line T47D

We have investigated the cell growth inhibitory effects of crude catechin (catechin) containing approximately 53% of epigallocatechin-3-gallate (EGCG) on the human breast cancer cell line T47D, and the mechanism of its action, with emphasis on the cell cycle and mitogen-activated protein kinases (MAPK). A significant dose-dependent growth inhibition was observed after treatment with catechin. At 48 h after the addition of catechin, cells at the G2/M phase were increased by 8.3%, compared with the control. Analysis of the expression of cell cycle-related proteins after the addition of catechin showed that the cyclin-dependent kinase (cdk) 2 and the cdk4 proteins were decreased after administration, the expression of cyclin A protein was increased at 24 h after administration, however, the expression of the cyclin D1 and cyclin E proteins was unchanged. At 24 h after the administration of catechin, the phosphorylation of cell division cycle 2 (cdc2) was inhibited, and the expression of cyclin B1 protein was also decreased. Furthermore, the analysis of the MAPK expression showed that the phosphorylated JNK/SAPK protein began to increase at 3 h after catechin administration, and the expression persisted until 24 h after administration, then decreased. The phosphorylation of p38 protein was increased at 12 h, and began to decrease at 36 h after catechin administration. Based on these results, we speculate that, in the breast cancer cell line T47D, catechin phosphorylated JNK/SAPK and p38, and that the phosphorylated JNK/SAPK and p38 inhibited the phosphorylation of cdc2, and regulated the expression of cyclin A, cyclin B1, and cdk proteins, thereby causing G2 arrest. The results suggested that catechin (EGCG) may be an effective adjuvant therapy after breast cancer surgery.     

Caveolin-3 is Up-Regulated in the Physiological Left Ventricular Hypertrophy Induced by Voluntary Exercise Training in Rats

Various substances have been introduced in relation with cardiac hypertrophy almost always with controversy in their roles in signal transduction. Those controversies may attribute to the diversity of cardiac hypertrophy. We previously showed that calcineurin was activated in physiological left ventricular hypertrophy (LVH) induced by voluntary exercise training, but not in decompensated pressure-overload LVH. In the current study, we advanced our search for the differences between the voluntary exercise-induced LVH and the pressure-overload LVH into several other hypertrophy-related substances including caveolin. Wistar rats were assigned to one of the following three groups: 10 weeks of voluntary exercise (EX), sedentary regimen (SED), and 4 weeks of ascending aortic constriction (AC). The EX rats voluntarily ran 1.6 ± 1.1 km/day in the specially manufactured cages resulting in LVH (24 % increase in left ventricular weight per body weight ratio). Myocardial tissue homogenate of the EX rats revealed different characteristics in signal transduction of hypertrophy from that of the AC. The EX rats had normal sarcoplasmic reticulum (SR) Ca²⁺ATPase mRNA level and normal myosin heavy chain isozyme pattern assessed by RNA protection assay, while AC rats had decreased SR Ca²⁺ATPase mRNA level and increased beta myosin heavy chain mRNA level. Myocardial caveolin-3 protein levels assessed by Western blotting increased in the EX rats but decreased in the AC rats. The voluntary exercise-induced LVH differed in signal transduction from the decompensated pressure-overload LVH. Caveolin-3 was induced in the voluntary exercise-induced LVH, while it was decreased in the decompensated pressure-overload LVH.Key Words: Exercise, hypertrophy, signal transduction     

Inhibitory Effects of Toremifene on N-Methyl-N-nitrosourea and Estradiol-17β-induced Endometrial Carcinogenesis in Mice

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg/30 g body weight) decreased expression of c- fos , interleukin (IL)-1α, estrogen receptor (ER)-α mRNAs and corresponding proteins induced by estradiol-l7β (E₂), in the uteri of the ovariectomized mice. Expression of ER-β mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N -methyl N -nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E₂ diet (5 ppm) plus TOR (0.2 mg/30 g body weight, subcutaneously, every four weeks); group 2, E₂ diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E₂-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c- fos as well as IL-1α expression induced by E₂. Such suppressive effects of TOR may be related to the decreased ER-α and increased ER-β expressions.     

Clinical implications of expression of ETS-1 related to angiogenesis in uterine endometrial cancers.

BACKGROUND: Angiogenesis is essential for development, growth and advancement of solid tumors. During angiogenesis, ETS-1 is strongly expressed in vascular endothelial cells and the adjacent interstitial cells, while the inhibition of ETS-1 expression leads to suppression of angiogenesis. This prompted us to study the clinical implications of ETS-1 in relation to angiogenesis in uterine endometrial cancers. PATIENTS AND METHODS: Sixty patients underwent resection for uterine endometrial cancers. From the tissues of 60 uterine endometrial cancers, the levels of ets-1 mRNA, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF) and interleukin (IL)-8 were determined by competitive RT-PCR using recombinant RNA and enzyme immunoassay, and the localization and counts of microvessel were determined by immunohistochemistry. RESULTS: There was a significant correlation between microvessel count and ets-1 gene expression levels in uterine endometrial cancers. Immunohistochemical staining revealed that the localization of ETS-1 was similar to that of vascular endothelial cells. The level of ets-1 mRNA tended to increase with increasing disease stage. Furthermore, the level of ets-1 mRNA correlated with levels of VEGF in well-differentiated adenocarcinomas (G1) and of bFGF in moderately differentiated adenocarcinomas (G2) and poorly differentiated adenocarcinomas (G3). CONCLUSIONS: ETS-1 is a possible angiogenic mediator in uterine endometrial cancers.