Piper sarmentosum inhibits ICAM-1 and Nox4 gene expression in oxidative stress-induced human umbilical vein endothelial cells

<p>Abstract</p> <p>Background</p> <p>Aqueous extract of <it>Piper sarmentosum </it>(AEPS) is known to possess antioxidant and anti-atherosclerotic activities but the mechanism responsible for it remains unclear. In early part of atherosclerosis, nuclear factor-kappa B (NF-κB) induces the expression of cellular adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin. NADPH oxidase 4 (Nox4) is the predominant source of superoxide in the endothelial cells whereas superoxide dismutase 1 (SOD1), catalase (CAT) and glutathione peroxidase (GPx) are the antioxidant enzymes responsible for inactivating reactive oxygen species. The present study aimed to investigate the effects of AEPS on the gene expression of NF-κB, VCAM-1, ICAM-1, E-selectin, Nox4, SOD1, CAT and GPx in cultured human umbilical vein endothelial cells (HUVECs).</p> <p>Methods</p> <p>HUVECs were divided into four groups:- control; treatment with 180 μM hydrogen peroxide (H₂O₂); treatment with 150 μg/mL AEPS and concomitant treatment with AEPS and H₂O₂for 24 hours. Total RNA was extracted from all the groups of HUVEC using TRI reagent. Subsequently, qPCR was carried out to determine the mRNA expression of NF-κB, VCAM-1, ICAM-1, E-selectin, Nox4, SOD1, CAT and GPx. The specificity of the reactions was verified using melting curve analysis and agarose gel electrophoresis.</p> <p>Results</p> <p>When stimulated with H₂O₂, HUVECs expressed higher level of ICAM-1 (1.3-fold) and Nox4 (1.2-fold) mRNA expression. However, AEPS treatment led to a reduction in the mRNA expression of ICAM-1 (p < 0.01) and Nox4 (p < 0.05) in the H₂O₂-induced HUVECs. AEPS also upregulated the mRNA expression of SOD1 (p < 0.05), CAT (p < 0.01) and GPx (p < 0.05) in oxidative stress-induced HUVECs. There was no significant change in the mRNA expression of VCAM-1 and E-selectin.</p> <p>Conclusion</p> <p>The expressional suppression of ICAM-1 and Nox4 and induction of antioxidant enzymes might be an important component of the vascular protective effect of AEPS.</p

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 1

Multidentate pyridinones inhibit the metabolism of nontransferrin-bound iron by hepatocytes and hepatoma cells

The therapeutic effect of iron (Fe) chelators on the potentially toxic plasma pool of nontransferrin-bound iron (NTBI), often present in Fe overload diseases and in some cancer patients during chemotherapy, is of considerable interest. In the present investigation, several multidentate pyridinones were synthesized and compared with their bidentate analogue, deferiprone (DFP; L1, orally active) and desferrioxamine (DFO; hexadentate; orally inactive) for their effect on the metabolism of NTBI in the rat hepatocyte and a hepatoma cell line (McArdle 7777, Q7). Hepatoma cells took up much less NTBI than the hepatocytes (&lt; 10%). All the chelators inhibited NTBI uptake (80-98%) much more than they increased mobilization of Fe from cells prelabelled with NTBI (5-20%). The hexadentate pyridinone, N,N,N-tris(3-hydroxy-1-methyl-2(1H)-pyridinone-4-carboxaminoethyl)amine showed comparable activity to DFO and DFP. There was no apparent correlation between Fe status, Fe uptake and chelator activity in hepatocytes, suggesting that NTBI transport is not regulated by cellular Fe levels. The intracellular distribution of iron taken up as NTBI changed in the presence of chelators suggesting that the chelators may act intracellularly as well as at the cell membrane. In conclusion (a) rat hepatocytes have a much greater capacity to take up NTBI than the rat hepatoma cell line (Q7), (b) all chelators bind NTBI much more effectively during the uptake phase than in the mobilization of Fe which has been stored from NTBI and (c) while DFP is the most active chelator, other multidentate pyridinones have potential in the treatment of Fe overload, particularly at lower, more readily clinically available concentrations, and during cancer chemotherapy, by removing plasma NTBI

Clinical perspectives on hereditary hemochromatosis

Hereditary hemochromatosis (HH) comprises a group of inherited disorders of iron metabolism that can result in progressive iron overload, morbidity, and mortality, generally in adulthood. HFE-related HH is the most common type of HH and will form the core of this discussion. The discovery of new proteins and gene mutations has defined other types of HH, termed non-HFE HH. The regulatory protein hepcidin has a central role in iron homeostasis in these disorders. While the liver is the predominant organ of iron deposition and iron-overload-related disease in HFE-related HH, involvement of extrahepatic tissue can also result in morbidity and mortality if the disorder is not diagnosed before organ damage develops. This review traverses the road from HFE genotype to phenotype with a focus on clinical penetrance, modifier factors for disease expression, and current thoughts and controversies on HH diagnosis and screening

Helical intensity-modulated radiotherapy with concurrent chemotherapy for oropharyngeal squamous cell carcinoma: a prospective investigation of acute swallowing and toxicity patterns

Background: Conformal radiotherapy modalities may minimize treatment toxicities. The purpose of this study was to document the extent and timing of dysphagia and related toxicities during helical intensity‐modulated radiotherapy (IMRT) with chemotherapy for oropharyngeal squamous cell carcinoma (SCC). Methods: We conducted a prospective study of 76 patients with oropharyngeal SCC undergoing helical IMRT with chemotherapy. Dysphagia and acute toxicity data were collected weekly during treatment and at 2, 4, and 12 weeks posttreatment using the Functional Oral Intake Scale, diet descriptors, and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: Patients experienced maximum incidence of grade 3 dysphagia (61%), mucositis (30%), and thick saliva (38%), with grade 2 xerostomia (87%) and dysgeusia (97%). Only 14.5% were nil‐by‐mouth. Symptoms peaked in week 7 and improved thereafter. Grade 3 dysphagia was twice as common for T3 to T4 tumors compared with T2. Conclusion: Results confirm that patients with oropharyngeal SCC undergoing helical IMRT with chemotherapy continue to experience incidences of acute toxicities comparable with other conformal techniques, and need supportive cares

Radiotherapy for cutaneous head and neck cancer and parotid tumours: a prospective investigation of treatment-related acute swallowing and toxicity patterns

Purpose: Reports of acute treatment-related dysphagia and toxicities for patients with parotid tumours or cutaneous head and neck cancer (HNC) are limited. This study aimed to describe the severity and timing of dysphagia and related toxicities experienced during radiotherapy for cutaneous HNC and parotid tumours, to inform the nature of future speech pathology (SP) service models required during treatment. Methods: Prospective study of 32 patients with parotid tumours and 36 with cutaneous HNC undergoing curative non-surgical management. Dysphagia and acute toxicity data was collected weekly during treatment and at 2, 4 and 12 weeks post-treatment using the Functional Oral Intake Scale, diet descriptors and CTCAE v4.0. Results: In both groups, minimal treatment toxicities (grades 0–1) were observed. Xerostomia and dysgeusia were the most frequently reported grade 2 toxicities. Only 3% of parotid patients and 6% with cutaneous HNC experienced grade 3 dysphagia. Full or soft texture diets were maintained by > 70% of patients in both groups. Symptoms peaked in the final week of treatment and rapidly improved thereafter. Apart from xerostomi

Dietary iron enhanced cyclin D1 expression and promoted epithelial cell apoptosis during acute colonic inflammation.

<p>Colonic mRNA expression of cell cycle regulators, cyclin D1 (A), cyclin B1 (B) and c-myc (C) were measured in Iron and Control (Ctrl) mice treated with or without DSS for 7 days. PCNA protein expression (D) was determined by immunoblot in isolated colonic epithelial cells from Iron/DSS and Ctrl/DSS mice compared with non-DSS treated mice at day 3. Apoptotic colonic epithelial cells were quantified (E) from TUNEL staining (F; representative images shown) of whole colonic Swiss roll preparations from Iron and Ctrl mice treated with or without DSS for 3 days. Results are expressed as mean±SEM, n = 3–8. * <i>P</i><0.05 denotes significance between DSS treatment versus no treatment; # <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl/DSS or Iron versus Ctrl mice. @ <i>P</i><0.05 denotes significance between Iron/DSS versus Ctrl. Scale bar denotes 50 µm.</p