Rapid activation of ERK1/2 and AKT in human breast cancer cells by cadmium

Cadmium (Cd), an endocrine disruptor, can induce a variety of signaling events including the activation of ERK1/2 and AKT. In this study, the involvement of estrogen receptors (ER) in these events was evaluated in three human breast caner cell lines, MCF-7, MDA-MB-231, and SK-BR-3. The Cd-induced signal activation patterns in the three cell lines mimicked those exhibited in response to 17β-estradiol. Specifically, treatment of MCF-7 cells, that express ERα, ERβ and GPR30, to 0.5–10 μM Cd for only 2.5 min resulted in transient phosphorylation of ERK1/2. Cd also triggered a gradual increase and sustained activation of AKT during the 60 min treatment period. In SK-BR-3 cells, that express only GPR30, Cd also caused a transient activation of ERK1/2, but not of AKT. In contrast, in MDA-MB-231 cells, that express only ERβ, Cd was unable to cause rapid activation of either ERK1/2 or AKT. A transient phosphorylation of ERα was also observed within 2.5 min of Cd exposure in the MCF-7 cells. While the estrogen receptor antagonist, ICI 182,780, did not prevent the effect of Cd on these signals, specific siRNA against hERα significantly reduced Cd-induced activation of ERK1/2 and completely blocked the activation of AKT. It is concluded that Cd, like estradiol, can cause rapid activation of ERK1/2 and AKT and that these signaling events are mediated by possible interaction with membrane ERα and GPR30, but not ERβ

Incidence of venous thromboembolism in cancer patients treated with cisplatin based chemotherapy - a cohort study

Background: Cancer related thrombosis not only increases morbidity and mortality but also poses a significant financial burden on health care system. Risk of venous thromboembolism (VTE) in these patients substantially increases with the addition of chemotherapy. Lately, cisplatin has been implicated as an independent factor. There is little data estimating the risk of venous thromboembolism in patients receiving cisplatin based chemotherapy when compared to other chemotherapeutic agents.Methods: Patients who had received chemotherapy between November 2010 and October 2012 were retrospectively identified from a single institute cancer registry. 200 patients who had received cisplatin based chemotherapy were identified as the exposed group while 200 patients who had received non-Cisplatin based regimens were identified as the non-exposed group. Patients were followed for development of VTE throughout the entire duration of therapy and one month thereafter. Cox proportional hazard model was used to compute relative risks with 95% confidence intervals.Results: The baseline characteristics were similar in the two groups. Mean age for the entire cohort was 55.4±10.7years and male to female ratio was almost 1:1. On univariate analysis, cisplatin based chemotherapy, presence of central venous catheter, female gender, poor performance status, high risk stratification according to the Khorana model and use of granulocyte colony stimulating factor were all significantly associated with the development of VTE. The crude relative risk for the incidence of VTE in cisplatin group was 2.8 (95% CI, 1.4 - 4.2) times compared to the non-Cisplatin group. When the relative risk was adjusted for the above variables in multivariable analysis, it increased to 3.3 (95% CI, 1.6 - 6.8) compared to the control group.CONCLUSION: A high incidence of VTE in patients receiving cisplatin based chemotherapy was demonstrated in this study. Prospective studies are warranted to establish this observation with certainty and to explore the possible use of thromboprophylaxis in patients receiving cisplatin based chemotherapeutic regimens

Avicennia marina and its sediments: potential indicators of heavy metal pollution

An ecological survey was carried out to determine the level of heavy metals in the mangrove flora and sediment along the Korangi creek (KC) and Sandspit back waters (SP) of the Karachi coast. The heavy metals included in this study are Fe, Mn, Zn, Pb, Cr, Co and Ni. The metal concentration was found to be higher in mangrove sediment than flora. Fe and Mn concentration were predominant at both the sampling sites whereas Co concentration was least. The study reveals the less contaminated area of Sandpit back water than of Korangi creek

MicroRNA-155 Attenuates Late Sepsis-Induced Cardiac Dysfunction Through JNK and β-Arrestin 2

Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression

Effects of a Standardized Phenolic-Enriched Maple Syrup Extract on β-Amyloid Aggregation, Neuroinflammation in Microglial and Neuronal Cells, and β-Amyloid Induced Neurotoxicity in \u3cem\u3eCaenorhabditis elegans\u3c/em\u3e

Published data supports the neuroprotective effects of several phenolic-containing natural products, including certain fruit, berries, spices, nuts, green tea, and olive oil. However, limited data are available for phenolic-containing plant-derived natural sweeteners including maple syrup. Herein, we investigated the neuroprotective effects of a chemically standardized phenolic-enriched maple syrup extract (MSX) using a combination of biophysical, in vitro, and in vivo studies. Based on biophysical data (Thioflavin T assay, transmission electron microscopy, circular dichroism, dynamic light scattering, and zeta potential), MSX reduced amyloid β1−42 peptide (Aβ1−42) fibrillation in a concentration-dependent manner (50–500 μg/mL) with similar effects as the neuroprotective polyphenol, resveratrol, at its highest test concentration (63.5 % at 500 μg/mL vs. 77.3 % at 50 μg/mL, respectively). MSX (100 μg/mL) decreased H2O2-induced oxidative stress (16.1 % decrease in ROS levels compared to control), and down-regulated the production of lipopolysaccharide (LPS)-stimulated inflammatory markers (22.1, 19.9, 74.8, and 87.6 % decrease in NOS, IL-6, PGE2, and TNFα levels, respectively, compared to control) in murine BV-2 microglial cells. Moreover, in a non-contact co-culture cell model, differentiated human SH-SY5Y neuronal cells were exposed to conditioned media from BV-2 cells treated with MSX (100 μg/mL) and LPS or LPS alone. MSX-BV-2 media increased SH-SY5Y cell viability by 13.8 % compared to media collected from LPS-BV-2 treated cells. Also, MSX (10 μg/mL) showed protective effects against Aβ1−42 induced neurotoxicity and paralysis in Caenorhabditis elegans in vivo. These data support the potential neuroprotective effects of MSX warranting further studies on this natural product

Anti-glycation and anti-oxidative effects of a phenolic-enriched maple syrup extract and its protective effects on normal human colon cells

Oxidative stress and free radical generation accelerate the formation of advanced glycation endproducts (AGEs) which are linked to several chronic diseases. Published data suggest that phenolic-rich plant foods, show promise as natural anti-AGEs agents due to their anti-oxidation capacities. A phenolic-enriched maple syrup extract (MSX) has previously been reported to show anti-inflammatory and neuroprotective effects but its anti-AGE effects remain unknown. Therefore, herein, we investigated the anti-glycation and anti-oxidation effects of MSX using biochemical and biophysical methods. MSX (500 μg mL−1) reduced the formation of AGEs by 40% in the bovine serum albumin (BSA)–fructose assay and by 30% in the BSA–methylglyoxal (MGO) assay. MSX also inhibited the formation of crosslinks typically seen in the late stage of glycation. Circular dichroism and differential scanning calorimeter analyses demonstrated that MSX maintained the structure of BSA during glycation. In the anti-oxidant assays, MSX (61.7 μg mL−1) scavenged 50% of free radicals (DPPH assay) and reduced free radical generation by 20% during the glycation process (electron paramagnetic resonance time scan). In addition, the intracellular levels of hydrogen peroxide induced reactive oxygen species were reduced by 27–58% with MSX (50–200 μg mL−1) in normal/non-tumorigenic human colon CCD-18Co cells. Moreover, in AGEs and MGO challenged CCD-18Co cells, higher cellular viabilities and rapid extracellular signal-regulated kinase (ERK) phosphorylation were observed in MSX treated cells, indicating its protective effects against AGEs-induced cytotoxicity. Overall, this study supports the biological effects of MSX, and warrants further investigation of its potential as a dietary agent against diseases mediated by oxidative stress and inflammation