N-acetyl Cysteine Overdose Induced Acute Toxicity and Hepatic Microvesicular Steatosis by Disrupting GSH and Interfering Lipid Metabolisms in Normal Mice.

N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, ß-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred ß-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.

Glioma-Associated Oncogene Homolog Inhibitors Have the Potential of Suppressing Cancer Stem Cells of Breast Cancer.

Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.

The association between lipid profiles and breast cancer among Taiwanese women.

BACKGROUND: Breast cancer incidence increased seven-fold from 1979 to 2002, and it has become the second most common cancer in Taiwanese women. Although the relationship between high-density lipoprotein cholesterol (HDL-C) and breast cancer has been studied, no consistent association has been explicitly confirmed. The aim of this study was to demonstrate the relationship between breast cancer and lipid profiles in Taiwanese women. METHODS: A total of 150 breast cancer patients before treatment and 71 healthy controls were enrolled. Lipid profiles in fasting serum were measured after participants gave their consent. RESULTS: The breast cancer patients had significantly lower values for HDL-C and apolipoprotein A-I (apoA-I), lower apoA-I/apoB ratios and higher values for very-low-density lipoprotein cholesterol (VLDL-C) than controls. After logistic regression analysis, the breast cancer patients had significantly higher values for VLDL-C and lower values for apoA-I after controlling for HDL-C and the apoA-I/apoB ratio. CONCLUSIONS: Our findings demonstrate that higher VLDL-C and lower apoA-I values were significantly associated with breast cancer, with a greater association between apoA-I values and the development of breast cancer than for HDL-C values.

Antioxidant status and superoxide anion radical generation in acute myeloid leukemia.

OBJECTIVES: This study was undertaken to investigate if there is a disparity in the antioxidant status and the ability of superoxide anion (O(2)(-)) generation in the patients with acute myeloid leukemia (AML). DESIGN AND METHODS: The peripheral blood samples from thirty AML patients and thirty-six healthy subjects were collected and leukocytes, erythrocytes and plasma were separated for use in various parameter measurements. RESULTS: The generation of O(2)(-), as reflected by lucigenin-based CL (LBCL), by the leukocytes of patients with AML was found to be significantly elevated either in resting or stimuli-elicited condition as compared with that of healthy controls (p<0.05). Coincidentally, these data were matched up with the suppressed SOD activities, notably in Cu/Zn SOD isoform found in AML patients (p<0.05). Conversely, SOD and GPx activities in erythrocytes of patients with AML were shown to be significantly higher than their normal counterparts (p<0.05). CONCLUSIONS: These data suggest that altered expression of antioxidant enzymes and higher capability of O(2)(-) generation by leukocytes seem to be a distinct feature of AML.

The clinical significance between activation of nuclear factor kappa B transcription factor and overexpression of HER-2/neu oncoprotein in Taiwanese patients with breast cancer.

BACKGROUND: This study investigated the role of nuclear factor-kappa B (NF-kappaB) activity in human breast cancer with overexpression of HER-2/neu oncoprotein, as well as its role on expression of different histological grades of cancer cells taken from Taiwanese breast cancer patients. MATERIALS AND METHODS: Specimens were collected from 82 female breast cancer patients. The HER-2/neu oncoprotein was measured by immunohistochemistry. NF-kappaB activity expression was assessed by the electrophoretic mobility shift assay, and confirmed by the supershift technique using anti-P65 antibody in both breast cancer tissue and the adjacent normal tissue. The histological grades were measured by Modified Bloom-Richardson Grading Scheme. RESULTS: Of the 82 cancer specimens, 81 (98.7%) showed higher or equal expressions of NF-kappaB activity when compared to the adjacent normal tissue. Fifty-five cases (67.1%) had higher levels of NF-kappaB activity in the cancerous tissue than in the adjacent normal tissue (p<0.005). With regard to tumor size, steroid receptors, stages, histological types, and node status, there were no statistically significant differences in NF-kappaB activity between cancerous tissues and adjacent normal tissues. However, significantly higher expressions of NF-kappaB activity were seen in those cases with positive HER2/neu oncoprotein, poorly differentiated histological grades, high nuclear pleomorphisms, and high mitotic counts (p<0.05). Positive HER-2/neu overexpression of oncoprotein had higher NF-kappaB activity (86%) than negative overexpression (60%) (p<0.05). It has been shown that the NF-kappaB activity increases in the HER-2/neu oncoprotein overexpression in human breast cancer. CONCLUSION: Overexpression of HER-2/neu gene could induce NF-kappaB activity in human breast cancer cells, as has been confirmed in other research on cell lines.