Hyperglycemia with severe reduction of plasma insulin level is frequently associated with acute ischemic heart disease. Since insulin is reported to be an anti thrombotic humoral factor, the mechanism of the impaired insulin synthesis was investigated. The plasma from the patients with acute myocardial infarction (AMI) was analyzed by SDS-polyacrylamide gel electrophoresis. Dermcidin isoform 2 (dermcidin) was determined by enzyme linked immunosorbent assay. Insulin synthesis was determined by in vitro translation of glucose induced insulin mRNA synthesis in the pancreatic β cells. Nitric oxide (NO) was determined by methemoglobin method. SDS-polyacrylamide gel electrophoresis of AMI plasma demonstrated the presence of a novel protein band of Mr 11 kDa that was determined to be dermcidin. Addition of 0.1 μM dermcidin inhibited insulin synthesis by >65 fold compared to control through the inhibition of NO synthesis in the pancreatic cells. The oral administration of 150 mg acetyl salicylic acid (aspirin) to the AMI patients increased the plasma insulin level from 13 (median) to 143 μunits/dl (median) with concomitant decrease of plasma dermcidin level from 112 to 9 nM in these patients within 12 h. It was also found that while the injection of 3.0 ± 0.05 (n = 10) nmol dermcidin with 0.25 ± 0.03 μmol ADP/g body weight caused coronary thrombus in mice, ADP itself at this concentration failed to produce thrombus. These results indicated that dermcidin was a novel platelet aggregating agent, and potentiated the ADP induced thrombosis in the animal model as well as acutely inhibited glucose induced insulin synthesis.

The role of aspirin-induced NO synthesis in the production of interferon-alpha (IFN-alpha) in leucocytes and the effect of IFN-alpha on platelet aggregation was studied. Treatment of Platelet Rich Plasma (PRP) with the dialyzed supernatant from the leucocyte suspension incubated with 80 microM aspirin resulted in parallel syntheses of NO and IFN-alpha as determined by methemoglobin assay and enzyme linked immunosorbent assay respectively. Incubation of PRP with 10 nM purified IFN-alpha for 40 min resulted in the maximal inhibition of platelet aggregation through the synthesis of NO due to the activation of nitric oxide synthase in platelets by IFN-alpha. The treatment of clotted PRP with IFN-alpha resulted in the lysis of the clot due to the fibrinolysis. Injection of IFN-alpha was found to protect mice from death due to the lysis of ADP-induced coronary thrombus. Interferon-alpha was found to be a potent inhibitor of platelet aggregation and a thromboprotective agent.

The effect of foods on the production of interferon-alpha (IFN-alpha) is currently unknown. Garlic (Allium sativum) used as a folk medicine is reported to stimulate nitric oxide (NO) production. We investigated the systemic increase of NO due to the ingestion of garlic on the plasma IFN-alpha level in normal volunteers. Normal volunteers (10 groups, 10 in each group) ate 2 g fresh garlic, and plasma NO and IFN-alpha levels were determined after 2 and 4 h. The participants were also asked to eat garlic for various periods of time, and plasma NO and IFN-alpha were similarly assayed. Ingestion of 2 g fresh, but not boiled, garlic was found to increase the basal plasma level of NO from 2.7 +/- 0.1 microM to 8.76 +/- 0.21 microM at 2 and 4 h, respectively. The basal plasma IFN-alpha level increased from 9.51 +/- 0.26 nM to 46.3 +/- 1.2 nM in normal volunteers (n = 10) at the same time. The chronic eating of garlic was found to maintain IFN-alpha at high levels for at least 7 days. The exposure of neutrophils to garlic in vivo or in vitro, which also stimulated synthesis of NO in these cells, was found to stimulate IFN-alpha synthesis as measured by the stimulation of IFN-alpha mRNA synthesis. Thus, consumption of garlic resulted in stimulated synthesis of NO and, in turn, IFN-alpha in humans, which could be beneficial in viral or proliferative diseases.

Purpose Estrogen, through its binding to nuclear estrogen receptor (ER), has been implicated in the development of human breast cancer. The presence or absence of ER in breast lesions has been used to classify breast cancer into ER+ or ER- type. Maspin, an anti-breast cancer protein produced in normal mammary cells, has also been reported to control the condition. Studies have been conducted to determine the role of ER+ and ER- status in neutrophils in the synthesis of maspin in human breast cancer. Methods Maspin presence was determined by enzyme linked immunosorbent assay, while nitric oxide (NO) level was determined using the methemoglobin method. Results Scatchard plots of the equilibrium binding of estrogen demonstrated the presence of 4.18×10 7 receptors per normal neutrophil and 2.46×10 7 receptors per ER+ neutrophil with a similar dissociation constant (0.926 nM). The ER- type showed nonspecific estrogen binding only. At 0.6 nM estrogen, NO synthesis was maximally increased to 1.829 and 0.887 µM NO/10 9 cells at 4 hours in normal and ER+ neutrophils respectively, with synthesis of 2.383 and 1.422 nM maspin in normal and ER+ neutrophils respectively. Estrogen failed to produce these effects in ER- neutrophils. Conclusion ER status in neutrophils determined maspin synthesis in breast cancer through the stimulation of NO synthesis. Neutrophils with ER- status which do not produce any maspin when treated with estrogen, might imply a worse prognostic outcome in ER- breast cancer due to the lack of anti-breast cancer protein synthesis.

Maspin, a 42 kDa protein produced in normal breast cells, has been shown to inhibit the invasion and metastasis of breast cancer in an animal model. Ingestion of acetylsalicylic acid (aspirin) by breast cancer patients has been reported to restore the systemic synthesis of maspin through the stimulation of systemic nitric oxide production. Studies were carried out to determine the effect of aspirin on the incidence of breast cancer metastasis, which is reported to occur in 50% of patients who have previously received chemotherapy, radiation, and ⁄ or surgery. Thirty-five female patients (aged 41-65 years) with breast cancer who had previously received these therapies took one 75 mg ⁄ 70 kg body weight enteric-coated aspirin tablet every 24 h, after an adequate meal, for 3 years. Their plasma nitric oxide and maspin levels were measured. The occurrence of metastasis was ascertained monthly by a qualified oncologist, and confirmed, if necessary, by biopsy. Daily ingestion of aspirin by participants resulted in an increase in maspin levels from 0.95 ± 0.04 to 4.63 ± 0.05 nM after 24 h. These levels were maintained for 3 years. These studies suggest that daily ingestion of aspirin might significantly reduce the incidence of breast cancer metastasis in patients who have previously received anticancer therapies. (Cancer Sci 2010; 101: 2105-2109 M ammary serpin (maspin), a serine proteinase inhibitor, has been reported to prevent ⁄ control breast cancer.( 1) This protein (42 kDa) is reported to be synthesized abundantly in normal mammary epithelial cells through the expression of maspin mRNA.(2,3) However, the synthesis of the protein is reported to progressively decrease with the progression of breast cancer.(2,3) Exogenously administered maspin in an animal model has been shown to reduce the growth and metastasis of breast cancer as well as to block tumor motility and invasion, (4,5) and the effect of maspin was reported to be reversed by the use of antimaspin antibody.(6) Considering the anticancer properties of maspin, it is possible to suggest that the protein plays a critically important role in the prevention of metastasis as well as in the development of breast cancer.It has been reported that the synthesis of this protein under physiological conditions is regulated by insulin-induced nitric oxide (NO) synthesis, and the impaired maspin synthesis in breast cancer (2,3) was related to the impairment of insulinreceptor interaction in the malignant cells, leading to impaired NO synthesis.(7) Maspin production in human breast cancer can be restored to normal ranges by using aspirin, which stimulates NO synthesis independently of the insulin receptor both in the case of malignant breast cancer cells in vitro, and in breast cancer patients who ingest the compound orally.(8) This effect of aspirin, resulting in the stimulation of NO synthesis in various cells, has been reported to be independent of the well-known effect of aspirin on the inhibition of prostaglandin synthesis. (9) Breast cancer is well known for its pr...

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These results suggest that estrogen and progesterone complement each other in NO-induced maspin synthesis, and do not necessarily antagonize in the synthesis of the anti-breast-cancer protein.