Javed Yasin

Contrasting actions of diesel exhaust particles on the pulmonary and cardiovascular systems and the effects of thymoquinone

BACKGROUND AND PURPOSE Acute exposure to particulate air pollution has been linked to acute cardiopulmonary events, but the underlying mechanisms are uncertain.

Evaluation of the direct systemic and cardiopulmonary effects of diesel particles in spontaneously hypertensive rats.

Recent data suggest that ultrafine pollutant particles (diameter <0.1microm) may pass from the lung into the systemic circulation. However, the systemic and cardiorespiratory effects of translocated particles are not well known. In this study, we determined the direct acute (24h) effect of the systemic administration of 0.01mg/kg and 0.02mg/kg diesel exhaust particles (DEP) on systolic blood pressure, heart rate, and both systemic and pulmonary inflammation in spontaneously hypertensive rats (SHR). Compared to the blood pressure in control group, rats exposed to DEP exhibited a dose-dependent increase in systolic blood pressure, at 0.01mg/kg (P<0.05) and 0.02mg/kg (P<0.01). Likewise, the heart rate was also dose-dependently increased at 0.01mg/kg (P:NS) and 0.02mg/kg (P<0.01) compared to control SHR. DEP exposure (0.02mg/kg) significantly elevated the number of leukocytes in blood (P<0.05), interleukin-6 (IL-6, P<0.005), tumor necrosis factor alpha (P<0.05) and leukotriene B4 (LTB4, P<0.005) concentrations in plasma. Moreover, in SHR given 0.02mg/kg, the number of platelet was significantly reduced (P<0.05), whereas the tail bleeding time was prolonged (P<0.05). Pulmonary inflammations were confirmed by the presence of a significant increase in the number of macrophages (0.02mg/kg) and neutrophils (0.01 and 0.02mg/kg) and protein contents (0.02mg/kg) in bronchoalveolar lavage (BAL) compared to saline-treated SHR. Also, IL-6 (0.01mg/kg; P<0.05 and 0.02mg/kg; P<0.01), LTB4 (0.02mg/kg; P<0.05) concentrations in BAL and the superoxide dismutase activity (0.02mg/kg; P=0.01) were significantly elevated compared to control group. We conclude that, in SHR, the presence of DEP in the systemic circulation leads not only to cardiac and systemic changes, but also triggers pulmonary inflammatory reaction involving IL-6, LTB4 and oxidative stress.

Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.

Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human breast cancer cell survival, migration and invasion in vitro, and on tumor growth in nude mice, using the human estrogen receptor-negative breast cancer cell line MDA-MB-231. The non-tumorigenic MCF10-A cell line derived from normal human mammary epithelium was used as control. Frondoside A (0.01-5 μM) decreased the viability of breast cancer cells in a concentration- and time-dependent manner, with 50%-effective concentration (EC50) of 2.5 μM at 24h. MCF10-A cells were more resistant to the cytotoxic effect of Frondoside A (EC50 superior to 5 μM at 24 h). In the MDA-MB-231 cells, Frondoside A effectively increased the sub-G1 (apoptotic) cell fraction through the activation of p53, and subsequently the caspases 9 and 3/7 cell death pathways. In addition, Frondoside A induced a concentration-dependent inhibition of MDA-MB-231 cell migration and invasion. In vivo, Frondoside A (100 μg/kg/dayi.p. for 24 days) strongly decreased the growth of MDA-MB-231 tumor xenografts in athymic mice, without manifest toxic side-effects. Moreover, we found that Frondoside A could enhance the killing of breast cancer cells induced by the chemotherapeutic agent paclitaxel. These findings identify Frondoside A as a promising novel therapeutic agent for breast cancer.

Amorphous silica nanoparticles impair vascular homeostasis and induce systemic inflammation

Amorphous silica nanoparticles (SiNPs) are being used in biomedical, pharmaceutical, and many other industrial applications entailing human exposure. However, their potential vascular and systemic pathophysiologic effects are not fully understood. Here, we investigated the acute (24 hours) systemic toxicity of intraperitoneally administered 50 nm and 500 nm SiNPs in mice (0.5 mg/kg). Both sizes of SiNPs induced a platelet proaggregatory effect in pial venules and increased plasma concentration of plasminogen activator inhibitor-1. Elevated plasma levels of von Willebrand factor and fibrinogen and a decrease in the number of circulating platelets were only seen following the administration of 50 nm SiNPs. The direct addition of SiNPs to untreated mouse blood significantly induced in vitro platelet aggregation in a dose-dependent fashion, and these effects were more pronounced with 50 nm SiNPs. Both sizes of SiNPs increased lactate dehydrogenase activity and interleukin 1β concentration. However, tumor necrosis factor α concentration was only increased after the administration of 50 nm SiNPs. Nevertheless, plasma markers of oxidative stress, including 8-isoprostane, thiobarbituric acid reactive substances, catalase, and glutathione S-transferase, were not affected by SiNPs. The in vitro exposure of human umbilical vein endothelial cells to SiNPs showed a reduced cellular viability, and more potency was seen with 50 nm SiNPs. Both sizes of SiNPs caused a decrease in endothelium-dependent relaxation of isolated small mesenteric arteries. We conclude that amorphous SiNPs cause systemic inflammation and coagulation events, and alter vascular reactivity. Overall, the effects observed with 50 nm SiNPs were more pronounced than those with 500 nm SiNPs. These findings provide new insight into the deleterious effect of amorphous SiNPs on vascular homeostasis.

Diesel exhaust particles in the lung aggravate experimental acute renal failure

Inhaled particles are associated with pulmonary and extrapulmonary effects. Also, acute renal failure (ARF) is associated with increased mortality, related to pulmonary complications. Here, we tested the possible potentiating effect of diesel exhaust particles (DEP) in an animal model of ARF induced by a single ip injection of cisplatin (CP, 6 mg/kg) in rats. Six days later, the rats were intratracheally instilled with either DEP (0.5 or 1 mg/kg) or saline (control) and renal, systemic, and pulmonary variables were studied 24 h thereafter. CP increased the serum concentrations of urea and creatinine and reduced glutathione (GSH) concentration and superoxide dismutase activity in renal cortex. CP caused renal tubular necrosis; increased urine volume, protein concentrations, and N-acetyl-beta-D-glucosaminidase (NAG) activity; and decreased urine osmolality. The combination of DEP and CP aggravated the CP-induced effects on serum urea and creatinine, urine NAG activity, and renal GSH. The arterial O(2) saturation and PO(2) were significantly decreased in CP + DEP versus CP + saline and CP + DEP versus DEP. The number of platelets was reduced in DEP compared to saline-treated rats and CP + DEP versus DEP alone or CP + saline. Increases in macrophage and neutrophils numbers in bronchoalveolar lavage were found in DEP versus saline group and CP + DEP versus CP. Histopathological changes in lungs of DEP-treated rats were aggravated by the combination of CP + DEP. These included marked interstitial cell infiltration and congestion. We conclude that the presence of DEP in the lung aggravated the renal, pulmonary, and systemic effects of CP-induced ARF.

Short-Term Systemic Effects of Nose-Only Cigarette Smoke Exposure in Mice: Role of Oxidative Stress

Background/Aims: Long–term cigarette smoking (CS) is a major risk factor for respiratory and cardiovascular diseases, and is also known to adversely affect other organs. However, data on the systemic effects of short-term CS exposure (STCSE) are scarce. Presently, using a nose-only exposure system, we evaluated the systemic effects of STCSE in mice. Methods: We assessed the effects of CS generated by 9 consecutive cigarettes per day for 4 days in a nose-only exposure system on cardiovascular, hepatic and renal endpoints evaluated on day 5 in mice. Control mice were exposed to air only. Results: CS significantly increased systolic blood pressure and decreased total nitric oxide plasma concentration. Circulating platelets and erythrocyte numbers were also increased. However, STCSE did not significantly increase thrombosis in pial arterioles and venules. STCSE significantly raised plasma alanine aminotransferase and gamma glutamyl transpeptidase activities, but did not affect urea or creatinine concentrations. Interestingly, while STCSE enhanced the production of reactive oxygen species in heart and kidney and lipid peroxidation in heart, liver and kidneys, it also enhanced the antioxidant activity of superoxide dismutase, probably indicating that STCSE causes adaptive reactions to counterbalance the potentially damaging action of oxygen radicals induced by STCSE. Conclusion: These results suggest that STCSE causes blood pressure increase, hepatotoxicity and oxidative stress in the heart, liver and the kidneys. These data provide information on the initial steps leading to the systemic effects of STCSE, a stage at which the diseases may likely be reversed.

Oxidative stress, inflammation, and DNA damage in multiple organs of mice acutely exposed to amorphous silica nanoparticles

The use of amorphous silica (SiO2) in biopharmaceutical and industrial fields can lead to human exposure by injection, skin penetration, ingestion, or inhalation. However, the in vivo acute toxicity of amorphous SiO2 nanoparticles (SiNPs) on multiple organs and the mechanisms underlying these effects are not well understood. Presently, we investigated the acute (24 hours) effects of intraperitoneally administered 50 nm SiNPs (0.25 mg/kg) on systemic toxicity, oxidative stress, inflammation, and DNA damage in the lung, heart, liver, kidney, and brain of mice. Lipid peroxidation was significantly increased by SiNPs in the lung, liver, kidney, and brain, but was not changed in the heart. Similarly, superoxide dismutase and catalase activities were significantly affected by SiNPs in all organs studied. While the concentration of tumor necrosis factor α was insignificantly increased in the liver and brain, its increase was statistically significant in the lung, heart, and kidney. SiNPs induced a significant elevation in pulmonary and renal interleukin 6 and interleukin-1 beta in the lung, liver, and brain. Moreover, SiNPs caused a significant increase in DNA damage, assessed by comet assay, in all the organs studied. SiNPs caused leukocytosis and increased the plasma activities of lactate dehydrogenase, creatine kinase, alanine aminotranferase, and aspartate aminotransferase. These results indicate that acute systemic exposure to SiNPs causes oxidative stress, inflammation, and DNA damage in several major organs, and highlight the need for thorough evaluation of SiNPs before they can be safely used in human beings.

Airway resistance, inflammation and oxidative stress following exposure to diesel exhaust particle in angiotensin II-induced hypertension in mice

Exposure to particulate matter is a risk factor for respiratory and cardiovascular diseases. However, the mechanisms underlying these effects are not well understood. Here, we compared the impact of diesel exhaust particles (DEP) on airway resistance, inflammation and oxidative stress in normal mice, or mice made hypertensive by implanting osmotic minipump infusing angiotensin II. On day 13 after the onset of infusion, angiotensin II induced significant increase in heart rate (P<0.05) and systolic blood pressure (P<0.0001). On the same day, mice were intratracheally instilled with either DEP (15 μg/mouse) or saline. Twenty-four hour later, the measurement of airway reactivity to methacholine (0-10mg/ml) in vivo by a forced oscillation technique showed a significant and dose dependent increase in airway resistance in normotensive mice exposed to DEP compared to those exposed to saline. In hypertensive mice, there was no difference in airway resistance in DEP versus saline exposed mice. However, following exposure to DEP, airway resistance significantly increased in normotensive versus hypertensive mice. Bronchoalveolar lavage (BAL) fluid analysis showed a significant increase in macrophage numbers in normotensive mice exposed to DEP compared to those exposed to saline, and to hypertensive mice exposed to DEP. Neutrophil numbers were significantly increased in both normotensive and hypertensive mice exposed to DEP compared with their respective control groups. Superoxide dismutase activity was significantly decreased following DEP exposure in both normotensive and hypertensive mice compared to their respective controls. However, total proteins, a marker for increase of epithelial permeability, and malondialdehyde, a reflection of lipid peroxidation, were only increased in normotensive mice exposed to DEP. Therefore, our data suggest that DEP do not aggravate airway resistance and inflammation in angiotensin II-induced hypertensive mice. On the contrary, at the dose of DEP and time point investigated, airway resistance, inflammation and oxidative stress are increased in normotensive compared to hypertensive mice.

Ameliorative effect of chrysin on adenine-induced chronic kidney disease in rats

Chrysin (5, 7- dihydroxyflavone) is a flavonoid with several pharmacological properties that include antioxidant, anti-inflammatory and antiapoptotic activities. in this work, we investigated some effects of three graded oral doses of chrysin (10, 50 and 250 mg/kg) on kidney structure and function in rats with experimental chronic renal disease (CKD) induced by adenine (0.25% w/w in feed for 35 days), which is known to involve inflammation and oxidative stress. Using several indices in plasma, urine and kidney homogenates, adenine was found to impair kidney function as it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and N-Acetyl-beta-D-glucosaminidase activity. Furthermore, it raised plasma concentrations of the uremic toxin indoxyl sulfate, some inflammatory cytokines and urinary albumin concentration. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activities, total antioxidant capacity and reduced glutathione were all adversely affected. Most of these adenine – induced actions were moderately and dose -dependently mitigated by chrysin, especially at the highest dose. Chrysin did not cause any overt adverse effect on the treated rats. The results suggest that different doses of chrysin produce variable salutary effects against adenine-induced CKD in rats, and that, pending further pharmacological and toxicological studies, its usability as a possible ameliorative agent in human CKD should be considered.

Interaction of Amorphous Silica Nanoparticles with Erythrocytes in Vitro: Role of Oxidative Stress

Background/Aims: The use of engineered nanomaterials in the form of nanoparticles (NP) for various biomedical applications, as well as in consumer products, has raised concerns about their safety for human health. These NP are intended to be administered directly into the circulation following intravenous injection, or they may reach the circulation following other routes of administration such as oral or inhalation, and interact with circulating cells such as erythrocytes. However, little is known about the interaction of amorphous SiNP with erythrocytes. Methods: We studied the interaction of amorphous silica nanoparticles (SiNP) at various concentrations (1, 5, 25 and 125µg/ml) with mouse erythrocytes in vitro. Results: Incubation of erythrocytes with SiNP caused a dose-dependent hemolytic effect. Likewise, the activity of lactate dehydrogenase was dose-dependently increased by SiNP. Transmission electron microscopy analysis revealed that SiNP are taken up by erythrocytes. Lipid erythrocyte susceptibility to in vitro peroxidation measured by malondialdehyde showed a significant and dose-dependent increase in erythrocytes. SiNP also enhanced the antioxidant activities of superoxide dismutase (SOD), catalase and reduced glutathione (GSH). Moreover, SiNP increased caspase 3, triggered annexin V-binding and caused a dose-dependent increase of cytosolic calcium concentration. Conclusion: It can be concluded that SiNP cause a dose-dependent hemolytic activity and are taken up by the erythrocytes. We also found that SiNP induce the occurrence of oxidative activity, apoptosis and increase cytosolic Ca2+, which may explain their haemolytic activity. Our in vitro data suggest that SiNP may, plausibly, lead to anemia and circulatory disorders in vivo.