LiCl at doses sufficient to induce conditioned taste aversion (CTA) causes c-Fos expression in the brain regions implicated in CTA formation. It has been reported that nitric oxide (NO) may play a role in CTA learning and LiCl increases both the synthesis and activity of NO synthase (NOS) in the brain. In this study, we examined the effect of central N omega-nitro-L- arginine methyl ester (L-NAME) on the brain c-Fos expression and CTA learning induced by lithium in rats. In the results, intracerebroventricular L-NAME given prior to lithium did not change either the lithium-induced CTA or c-Fos in the relevant brain regions. This suggests that the brain NO system may not be involved in the neuronal activation during lithium-induced CTA formation.
Animals ; Avoidance Learning/*drug effects/physiology ; Brain/*physiology ; Conditioning (Psychology) /*drug effects/physiology ; Immunohistochemistry ; Injections, Intraventricular ; Lithium/*pharmacology ; Male ; NG-Nitroarginine Methyl Ester/*pharmacology ; Nitric Oxide/physiology ; Proto-Oncogene Proteins c-fos/*analysis ; Rats ; Rats, Sprague-Dawley ; Support, Non-U.S. Gov't ; Taste/*drug effects/physiology

Bone morphogenic protein 4 (BMP4), a member of the TGF-beta superfamily, induced neural differentiation of neural stem cells (NSCs) grown in a medium containing basic fibroblast growth factor (bFGF). The Ras protein level and the activities of the downstream ERKs were increased by transfection of BMP4 or treatment with recombinant BMP4. The effects of BMP4, including activation of the Ras-ERK pathway and induction of the neuron marker beta-tubulin type III (Tuj1), were blocked by co-treatment of the BMP4 antagonist, noggin. The roles of the Ras-ERK pathway in neuronal differentiation by BMP4 were revealed by measuring the effect of the ERK pathway inhibition by dominant negative Ras or PD98059, the MEK specific inhibitor. BMP4 is a transcriptional target of Wnt/beta-catenin signaling, and both the mRNA and protein levels of BMP4 were increased by treatment of valproic acid (VPA), a chemical inhibitor of glycogen synthase kinase 3beta (GSK3beta) activating the Wnt/beta-catenin pathway. The BMP4- mimicking effects of VPA, activation of the Ras-ERK pathway and induction of Tuj1, also were blocked by noggin. These results indicate the potential therapeutic usage of VPA as a replacement for BMP4.
Animals ; Bone Morphogenetic Protein 4/genetics/*metabolism ; Cell Differentiation/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology/embryology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Neurons/*cytology ; Rats ; Rats, Sprague-Dawley ; Stem Cells/*cytology ; Up-Regulation/drug effects ; Valproic Acid/pharmacology ; beta Catenin/metabolism ; ras Proteins/genetics/metabolism

Butylated hydroxytoluene (BHT) can inhibit experimental atherosclerosis in animals. Although the agent is an antioxidant, the exact mechanism of the reaction in atherosclerosis is still unknown. To investigate the effects of BHT on expression of P-selectin (PADGEM, GMP-140), intercellular adhesion molecule-1 (ICAM-1) and class II MHC (Ia) antigen, we proposed an experiment on rats. Male rats (n=18 per group) were fed either a normal cholesterol control diet, a normal cholesterol diet containing 0.5% BHT (BD), a high cholesterol diet containing 1.5% cholesterol and 0.1% sodium cholate (CD), or the CD diet containing 0.5% BHT (BCD). Rats were sacrificed after 3 days, and after 1, 2, 4, 10, and 17 weeks of dietary treatment. Although there was no gross or light microscopic atherosclerotic lesions, scanning electron microscopy revealed monocytic adhesion to aortic endothelium and mild endothelial injuries in CD and BCD groups. Immunohistochemically, the addition of BHT to a high cholesterol diet inhibited P-selectin expression but not in ICAM-1 and Ia antigen. These findings suggest that in rats, high cholesterol diets induce expression of ICAM-1, P-selectin and Ia antigen. In addition, the antiatherogenic effect of BHT may play a role in the inhibition of P-selectin.
Animal ; Antioxidants/pharmacology ; Antioxidants/metabolism* ; Aorta, Abdominal/ultrastructure ; Aorta, Abdominal/pathology ; Aorta, Thoracic/ultrastructure ; Aorta, Thoracic/pathology ; Butylated Hydroxytoluene/pharmacology ; Butylated Hydroxytoluene/metabolism* ; Cholesterol/metabolism ; Cholesterol, Dietary/metabolism* ; Male ; Microscopy, Electron, Scanning ; P-Selectin/biosynthesis* ; Rats ; Rats, Sprague-Dawley

PURPOSE: A new therapeutic approach is needed in patients with metastatic renal cell carcinoma (RCC) because of a dismal prognosis. MN/CA9 is a transmembrane glycoprotein that was first identified in the human cervical carcinoma cell line, HeLa. Since MN/CA9 protein is highly expressed in RCC tissues, but not in normal kidney, we constructed a tumor-specific replication-competent adenoviral vector utilizing MN/CA9 promoter (Ad-MN/CA9-E1a) and demonstrated its selective cytotoxicity toward MN/CA9-expressing RCC cells in vitro. MATERIALS AND METHODS: MN/CA9-positive (HeLa, SK-RC-52) and MN/ CA9-negative (SK-RC-29) cells were used. RT-PCR assay for MN/CA9 mRNA was performed in each cells. Ad5 E1a protein production in each cells after infection with Ad-MN/CA9-E1a was determined by western blot analysis. In vitro cytotoxicity assay was performed for assessing the selective cytotoxicity of Ad-MN/CA9-E1a to MN/CA9-expressing cells. RESULTS: RT-PCR assay showed that a distinct 255-bp fragment corresponding to the sequence within MN/CA9 cDNA was detected in HeLa and SK-RC-52 cells, but SK-RC-29 cells did not have MN/CA9 transcripts. Western blot analysis demonstrated that HeLa and SK-RC-52 cells showed much stronger Ad5 E1a protein expressions compared with SK-RC-29. In vitro cytotoxicity assay revealed that the growth of MN/CA9-positive cells was significantly inhibited with 0.1-1MOI of Ad-MN/CA9-E1a, but the growth of MN/CA9-negative cells (SK-RC-29) could only be inhibited by as many as 100MOI. CONCLUSIONS: These results suggest that a novel replication-competent adenoviral vector mediated by MN/CA9 promoter, Ad-MN/CA9-E1a, can selectively replicate in MN/CA9-expressing cancer cells with cytotoxic effects and may be utilized for the treatment of RCC.
Adenoviridae* ; Blotting, Western ; Carcinoma, Renal Cell* ; Cell Line ; DNA, Complementary ; Genetic Therapy* ; Glycoproteins ; Humans ; Kidney ; Prognosis ; RNA, Messenger ; Virus Replication

No abstract available.
Hong Kong* ; Rehabilitation* ; Stroke*

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
Male ; Humans ; Prostatic Neoplasms/pathology* ; Androgen Antagonists/therapeutic use* ; Prostate-Specific Antigen ; Castration ; Prostatic Neoplasms, Castration-Resistant/drug therapy*