Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells

Constitutive activation of extracellular signal regulated kinase (ERK)-Jun NH2-terminal kinase (JNK) signaling commonly occurs in tumors. The activation of ERK promotes cell proliferation, whereas that of JNK induces cell apoptosis. However, the apoptotic mechanism of ERK-JNK signaling in cancer is not well understood. Recently, we identified that apoptosis and activation of the JNK signaling pathway were induced after cordycepin treatment in human renal cancer, suggesting that JNK signaling might contribute to TK-10 cell apoptosis. We investigated the apoptotic effects of cordycepin by evaluating the activation of the ERK-JNK signaling pathway in renal cancer TK-10 cells. We found that cordycepin downregulated ERK and DUSP5, upregulated phosphorylated-JNK (p-JNK), and induced apoptosis. Moreover, we showed that siRNA-mediated inhibition of ERK downregulated DUSP5, whereas ERK overexpression upregulated DUSP5, and that DUSP5 knockdown by siRNA upregulated p-JNK. The JNK-specific inhibitor SP600125 upregulated nuclear translocation of β-catenin, and downregulated Dickkopf-1 (Dkk1), which has been shown to be a potent inhibitor of Wnt signaling. Dkk1 knockdown by siRNA upregulated nuclear β-catenin, suggesting the involvement of the Wnt/β-catenin signaling pathway. DUSP5 overexpression in TK-10 cells decreased p-JNK and increased nuclear β-catenin. The decreased Bax activation markedly protected against cordycepin-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Taken together, we show that JNK signaling activation by cordycepin mediated ERK inhibition, which might have induced Bax translocation and caspase-3 activation via regulation of DUSP5 in TK-10 cells, thereby promoting the apoptosis of TK-10 cells. Targeting ERK-JNK signaling via the apoptotic effects of cordycepin could be a potential therapeutic strategy to treat renal cancer

Dose-Dependent Neuroprotective Effect of Standardized Bee Venom Phospholipase A2 Against MPTP-Induced Parkinson’s Disease in Mice

Parkinson’s disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons within the substantia nigra (SN). While the precise etiology of dopaminergic neuronal demise is elusive, multiple lines of evidence indicate that neuroinflammation is involved in the pathogenesis of PD. We have previously demonstrated that subcutaneous administration of bee venom (BV) phospholipase A2 (bvPLA2) suppresses dopaminergic neuronal cell death in a PD mouse model. In the present study, we established standardized methods for producing bvPLA2 agent isolated from crude BV at good manufacturing practice (GMP) facility. The therapeutic efficacy of purified bvPLA2 agent was examined in MPTP-induced PD mice. Importantly, administration of purified bvPLA2 in a dose-dependent manner reversed motor deficits in PD mice as well as inhibited loss of dopaminergic neurons within the SN of PD mice. The concentration-dependent action of standardized bvPLA2 appeared to be related to the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs), which, in part, inhibits T helper 1 (Th1) and Th17 polarization and suppresses microglial activation in PD mice. Taken together, these results suggest that standardized bvPLA2 purified from BV shows a neuroprotective effect against PD and thus has a potential target for treatment of PD

A Korean Female Patient with Thiamine-responsive Pyruvate Dehydrogenase Complex Deficiency Due to a Novel Point Mutation (Y161C)in the PDHA1 Gene

Pyruvate dehydrogenase complex (PDHC) deficiency is mostly due to mutations in the X-linked E1α subunit gene (PDHA1). Some of the patients with PDHC deficiency showed clinical improvements with thiamine treatment. We report the results of biochemical and molecular analysis in a female patient with lactic acidemia. The PDHC activity was assayed at different concentrations of thiamine pyrophosphate (TPP). The PDHC activity showed null activity at low TPP concentration (1×10-3 mM), but significantly increased at a high TPP concentration (1 mM). Sequencing analysis of PDHA1 gene of the patient revealed a substitution of cysteine for tyrosine at position 161 (Y161C). Thiamine treatment resulted in reduction of the patient's serum lactate concentration and dramatic clinical improvement. Biochemical, molecular, and clinical data suggest that this patient has a thiamine-responsive PDHC deficiency due to a novel mutation, Y161C. Therefore, to detect the thiamine responsiveness it is necessary to measure activities of PDHC not only at high but also at low concentration of TPP

Comparison of Video-Assisted Minilaparotomy, Open, and Laparoscopic Partial Nephrectomy for Renal Masses

∙ The authors have no financial conflicts of interest. Purpose: Minimally invasive management of small renal tumors has become more common. We compared the results of partial nephrectomy by video-assisted minilaparotomy surgery (VAMS), open, and laparoscopic techniques. Materials and Methods: We retrospectively compared clinicopathological, oncological, and functional outcomes in 271 patients who underwent partial nephrectomy for renal tumors a

Clinical Outcome of Veterans with Acute Coronary Syndrome Who Had Been Exposed to Agent Orange

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the components of Agent Orange, has been reported to be a deadly poison despite its presence at extremely small doses. TCDD is reported to cause various kinds of cancers and other harmful effects on humans. However, a correlation between exposure to TCDD and acute coronary syndrome (ACS) is not yet proven. Thus, we examined the correlation between exposure to TCDD and ACS through an analysis of coronary angiograms from veterans of the Vietnam War. Two hundred fifty-one consecutive men undergoing coronary angiograms owing to ACS between April 2004 and May 2009 at Gwangju Veterans Hospital were analyzed. Included subjects were between 50 and 70 years of age. The patients were divided into two groups: 121 patients who had been exposed to TCDD (Group I) and 130 patients who had not been exposed to TCDD (Group II). Clinical and coronary angiographic findings were evaluated. Baseline clinical characteristics, inflammatory markers, and echocardiographic parameters were not significantly different between the two groups. The incidence of hypertension (71.1% vs. 60.0%, p=0.039) and hyperlipidemia (27.3% vs. 16.9%, p=0.038) was higher in Group I than in Group II. Total occlusion, stent length, stent use, and coronary lesion characteristics were not significantly different between the two groups. The rate of major adverse cardiovascular events (MACE) had no relationship with exposure to TCDD. Exposure to TCDD might not affect severity or the rate of MACE in persons with ACS

Intracranial metastasis from primary transitional cell carcinoma of female urethra: case report & review of the literature

<p>Abstract</p> <p>Background</p> <p>Transitional cell carcinoma (TCC) of the female urethra is a rare urological malignancy, and intracranial metastasis of this cancer has not yet been reported in the literature. This review is intended to present a case of multiple intracranial metastasis in a female patient with a remote history of primary urethral TCC.</p> <p>Case Presentation</p> <p>A 49-year-old woman, presented with a prolapsed mass in urethral orifice that was diagnosed as primary urethral TCC with distant lung and multiple bone metastases. The patient subsequently underwent chemotherapy under various regimens. A year later, the patient developed headache and vomiting which as was found to be due to multiple intracranial metastasis. The patient underwent surgical resection of the largest lesion located on the cerebellum, and consecutively gamma knife radiosurgery was performed for other small-sized lesions. Pathological examination of the resected mass revealed a metastatic carcinoma from a known urethral TCC. Serial work-up of systemic metastasis revealed concomitant aggravation of lung, spleen, and liver metastasis. The patient died of lung complication 2 months after the diagnosis of brain metastasis.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first reported case of cerebral metastasis from primary urethral TCC, with pathological confirmation. As shown in intracranial metastasis of other urinary tract carcinoma, this case occurred in the setting of uncontrolled systemic disease and led to dismal prognosis in spite of aggressive interventional modalities.</p