Asru K. Sinha

The Role of Dermcidin Isoform 2: A Two-Faceted Atherosclerotic Risk Factor for Coronary Artery Disease and the Effect of Acetyl Salicylic Acid on It

Hypertension and diabetes mellitus are considered to be two major atherosclerotic risk factors for coronary artery disease (CAD). A stress-induced protein identified to be dermcidin isoform 2 of Mr. 11u2009kDa from blood plasma of hypertensive persons when injected (0.1u2009μM) in rabbits increased the systolic pressure by 77% and diastolic pressure by 45% over the controls within 2u2009h. Ingestion of acetyl salicylic acid (150u2009mg/70u2009kg) by these subjects reduced systolic (130u2009mmu2009Hg) and diastolic pressures (80u2009mmu2009Hg) with reduction of plasma dermcidin level to normal ranges (9u2009nM). The protein was found to be a potent activator of platelet cyclooxygenase and inhibited insulin synthesis. Aspirin was found to reduce hypertension by reduction of plasma dermcidin level, neutralized the effect of cyclooxygenase, and restored the pancreatic insulin synthesis through NO synthesis. These results indicated that dermcidin could be a novel atherosclerotic risk factor for its hypertensive and diabetogenic effects.

Acetyl salicyclic acid (aspirin) improves synthesis of maspin and lowers incidence of metastasis in breast cancer patients

Maspin, a 42u2003kDa 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 41–65u2003years) with breast cancer who had previously received these therapies took one 75u2003mg/70u2003kg body weight enteric‐coated aspirin tablet every 24u2003h, after an adequate meal, for 3u2003years. 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 0.95u2003±u20030.04 to 4.63u2003±u20030.05u2003nM after 24u2003h. These levels were maintained for 3u2003years. 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)

The Role of Neutrophil Estrogen Receptor Status on Maspin Synthesis via Nitric Oxide Production in Human Breast Cancer

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 4.18×107 receptors per normal neutrophil and 2.46×107 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/109 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.

The thrombolytic effect of aspirin in animal model

BackgroundThe aspirin induced platelet aggregation has been reported to be mediated through the inhibition of platelet prostaglandin synthesis. This compound has also been recently reported to stimulate nitric oxide synthesis in platelets. Since nitric oxide has been reported to produce fibrinogen/fibrinolytic effect, investigation was carried out to determine fibrinolytic effect of in vivo exposure of platelets to aspirin in normal volunteers on the fibrinolysis of the clotted platelet-rich plasma in vitro. The thrombolytic effect of aspirin in situ was also carried out by injecting aspirin solution in the mice with ADP induced formed thrombi in the coronary artery.Methods and ResultsIt was found that the clotted platelet-rich plasma prepared from the volunteers (nxa0=xa010, Fxa0=xa05, Mxa0=xa05) who ingested 150xa0mg aspirin, began to undergo spontaneous and progressive fibrinolysis for 200xa0min at 37°C with the generation of fibrin degradation products in the lysate. No such fibrinolysis could be seen in control experiments. When platelet thrombi were produced in the coronary artery of mice by injecting ADP, and these animals subsequently received intravenous injection of aspirin (4xa0μM final), they not only survived (Pxa0<xa00.0001, nxa0=xa010) the thrombogenic assault but the lysis of the platelet thrombi was also noted in the post mortem examination. The thrombolytic effect of aspirin was found to be comparable to that of streptokinase in these animals.ConclusionsAspirin, through the stimulation of NO synthesis, may produce thrombolysis in vivo.

Dermcidin isoform-2 induced nullification of the effect of acetyl salicylic acid in platelet aggregation in acute myocardial infarction

The aggregation of platelets on the plaque rupture site on the coronary artery is reported to cause both acute coronary syndromes (ACS) and acute myocardial infarction (AMI). While the inhibition of platelet aggregation by acetyl salicylic acid was reported to produce beneficial effects in ACS, it failed to do in AMI. The concentration of a stress induced protein (dermcidin isoform-2) was much higher in AMI than that in ACS. Incubation of normal platelet rich plasma (PRP) with dermcidin showed one high affinity (Kd = 40u2005nM) and one low affinity binding sites (Kd = 333u2005nM). When normal PRP was incubated with 0.4u2005μM dermcidin, the platelets became resistant to the inhibitory effect of aspirin similar to that in the case of AMI. Incubation of PRP from AMI with dermcidin antibody restored the sensitivity of the platelets to the aspirin effect. Incubation of AMI PRP pretreated with 15u2005μM aspirin, a stimulator of the NO synthesis, resulted in the increased production of NO in the platelets that removed the bound dermcidin by 40% from the high affinity binding sites of AMI platelets. When the same AMI PRP was retreated with 10u2005μM aspirin, the aggregation of platelets was completely inhibited by NO synthesis.