Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes

Objectives: Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM). In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF) and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM) and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants. Design: CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26–47 years, BMI: 24.3–36.3 kg/m2) and 12 controls (age: 22–40 years, BMI: 30.1–37.0 kg/m2)]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA. Results: Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2–352.7) vs. 115.5 (60.5–188.7) pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3–0.6) vs. 0.8 (0.5–1.6); P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05). Conclusions: The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho-physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points

Excision of sympathetic ganglia and the rami communicantes with histological confirmation offers better early and late outcomes in Video assisted thoracoscopic sympathectomy

<p>Abstract</p> <p>Background</p> <p>Video-Assisted Thoracoscopic Sympathectomy (VATS) is an established minimally invasive procedure for thoracic sympathetic blockade in patients with hyperhidrosis, facial flushing and intractable angina. Various techniques using clips, diathermy and excision are used to perform sympathectomy. We present our technique of excision of the sympathetic chain with histological proof and the analysis of the early and late outcomes.</p> <p>Methods</p> <p>We evaluated 200 procedures in 100 consecutive patients, who underwent Video Assisted Thoracoscopic Sympathectomy by a single surgeon in our centre between September 1996 to March 2007. All patients had maximum medical therapy prior to surgery and were divided into 3 groups based on indications, Group 1(hyperhidrosis: 48 patients), Group 2 (facial flushing: 26 patients) and Group 3(intractable angina: 26 patients). The demography and severity of symptoms for each group were analysed. The endpoints were success rate, 30 day mortality, complications and patient's satisfaction.</p> <p>Results</p> <p>99 patients had bilateral VATS sympathectomy and 1 had unilateral sympathectomy. The conversion rate to open was 1(1%). All patients had successful removal of ganglia proven histologically with no perioperative mortality in our series. The complications included pneumothorax (5%), acute coronary syndrome (2%), transient Horner's syndrome (1%), transient paraesthesia (1%), wound infection (4%), compensatory hyperhidrosis (18%), residual flushing (3%) and wound pain (5%). There were five late deaths in the intractable angina group at a mean follow up of 36.7 months. Overall success rates of abolishing the symptoms were 96.3%, 87.5% and 95.2% for Group 1, 2 and 3 respectively.</p> <p>Conclusion</p> <p>Excision of the sympathetic chain with histological confirmation during VATS sympathectomy is a safe and effective method in treating hyperhidrosis, facial flushing and intractable angina with good long term results and satisfaction.</p

Studies on two polyherbal formulations (ZPTO and ZTO) for comparison of their antidyslipidemic, antihypertensive and endothelial modulating activities

Background Cardiovascular disorders (CVDs) are the leading cause of disease burden worldwide. Apart from available synthetic drugs used in CVDs, there are many herbal formulations including POL-10 (containing 10 herbs), which have been shown to be effective in animal studies but POL-10 was found to cause tachycardia in rodents as its side effect. This study was designed to modify the composition of POL-10 for better efficacy and/or safety profile in CVDs. Methods To assess the antidyslipidemic, antihypertensive and endothelial modulatory properties of two herbal formulations, (ZPTO and ZTO) containing Z: Zingiber officinalis, P: Piper nigrum, T: Terminalia belerica and O: Orchis mascula, different animal models including, tyloxapol and high fat diet-induced dyslipidemia and spontaneously hypertensive rats (SHR) were used. Effect on endothelial function was studied using isolated tissue bath set up coupled with PowerLab data acquisition system. The antioxidant activity was carried out using DPPH radical-scavenging assay. Results Based on preliminary screening of the ingredients of POL-10 in tyloxapol-induced hyperlipidemic rats, ZPTO and ZTO containing four active ingredients namely; Z, P, T and O were identified for further studies and comparison. In tyloxapol-induced hyperlipidemic rats, both ZPTO and ZTO caused significant reduction in serum triglyceride (TG) and total cholesterol (TC). In high fat diet-fed rats, ZPTO decreased TC, low-density lipoproteins cholesterol (LDL-C) and atherogenic index (AI). ZTO also showed similar effects to those of ZPTO with additional merits being more effective in reducing AI, body weight and more importantly raising high-density lipoproteins. In SHR, both formulations markedly reduced systolic blood pressure, AI and TG levels, ZTO being more potent in reversing endothelial dysfunction while was devoid of cardiac stimulatory effect. In addition, ZTO also reduced LDL-C and improved glucose levels in SHR. In DPPH radical-scavenging activity test, ZTO was also more potent than ZPTO. Conclusion The modified formulation, ZTO was not only found more effective in correcting cardiovascular abnormalities than ZPTO or POL-10 but also it was free from tachycardiac side-effect, which might be observed because of the presence of Piper nigrum in ZPTO

Development of Non-Natural Flavanones as Antimicrobial Agents

With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus. Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone. Through this study we have demonstrated that combinatorial synthesis of non-natural flavonones can identify novel antimicrobial agents with activity against bacteria and fungi but with minimal toxicity to human cells

Sociodemographic and Disease Correlates of Body Image Distress among Patients with Systemic Sclerosis

Body image concerns are infrequently studied in systemic sclerosis (SSc), even though significant visible disfigurement is common. The objective of this study was to identify sociodemographic and disease-related correlates of dissatisfaction with appearance and social discomfort among people with SSc.SSc patients came from the 15-center Canadian Scleroderma Research Group Registry. Sociodemographic information was based on patient self-report. Disease characteristics were obtained via physician examinations. The Brief-SWAP was used to assess dissatisfaction with appearance and social discomfort. Structural equation models were conducted with MPlus to determine the relationship of dissatisfaction with appearance and social discomfort with age, sex, education, marital status, race/ethnicity, disease duration, skin involvement, telangiectasias, skin pigmentation changes, and hand contractures.A total of 489 SSc patients (432 female, 57 male) were included. Extent of skin involvement was significantly associated with both dissatisfaction with appearance and social discomfort (standardized regression coefficients = 0.02, p = 0.001; 0.02, p = 0.020, respectively), as was skin involvement in the face (0.18, p = 0.016; 0.23, p = 0.006, respectively). Greater social discomfort was robustly associated with younger age (-0.017, p<0.001) and upper-body telangiectasias (0.32, p = 0.021). Dissatisfaction with appearance was associated with hand contractures (0.07, p = 0.036).This study found that dissatisfaction with appearance and social discomfort were associated with numerous disfiguring characteristics of SSc, in addition to age. These results underline that there are multiple factors contributing to body image distress in SSc, as well as the need to attend to both disease and social contexts in understanding the impact of disfigurement among patients

Predicted Relative Metabolomic Turnover (PRMT): determining metabolic turnover from a coastal marine metagenomic dataset

We present an approach in which the semantics of an XML language is defined by means of a transformation from an XML document model (an XML schema) to an application specific model. The application specific model implements the intended behavior of documents written in the language. A transformation is specified in a model transformation language used in the Model Driven Architecture (MDA) approach for software development. Our approach provides a better separation of three concerns found in XML applications: syntax, syntax processing logic and intended meaning of the syntax. It frees the developer of low-level syntactical details and improves the adaptability and reusability of XML applications. Declarative transformation rules and the explicit application model provide a finer control over the application parts affected by adaptations. Transformation rules and the application model for an XML language may be composed with the corresponding rules and application models defined for other XML languages. In that way we achieve reuse and composition of XML applications

Plant cell culture technology in the cosmetics and food industries : current state and future trends

The production of drugs, cosmetics, and food which are derived from plant cell and tissue cultures has a long tradition. The emerging trend of manufacturing cosmetics and food products in a natural and sustainable manner has brought a new wave in plant cell culture technology over the past 10 years. More than 50 products based on extracts from plant cell cultures have made their way into the cosmetics industry during this time, whereby the majority is produced with plant cell suspension cultures. In addition, the first plant cell culture-based food supplement ingredients, such as Echigena Plus and Teoside 10, are now produced at production scale. In this mini review, we discuss the reasons for and the characteristics as well as the challenges of plant cell culture-based productions for the cosmetics and food industries. It focuses on the current state of the art in this field. In addition, two examples of the latest developments in plant cell culture-based food production are presented, that is, superfood which boosts health and food that can be produced in the lab or at home

Ultrasound-assisted extraction of natural products

Ultrasound-assisted extraction (USAE) is an interesting process to obtain high valuable compounds and could contribute to the increase in the value of some food by-products when used as sources of natural compounds. The main benefits will be a more effective extraction, thus saving energy, and also the use of moderate temperatures, which is beneficial for heat-sensitive compounds. For a successful application of the USAE, it is necessary to consider the influence of several process variables, the main ones being the applied ultrasonic power, the frequency, the extraction temperature, the reactor characteristics, and the solvent-sample interaction. The highest extraction rate is usually achieved in the first few minutes, which is the most profitable period. 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Ultrason Sonochem 15:1075–1079Cárcel JA, Benedito J, Bon J, Mulet A (2007) High intensity ultrasound effects on meat brining. Meat Sci 76:611–619Cárcel JA, Benedito J, Rosselló C, Mulet A (2007) Influence of ultrasound intensity on mass transfer in apple immersed in a sucrose solution. J Food Eng 78:472–479Cavitus (2009) Grape colour and flavour extraction (Pat. Pend.) for red must extraction http://www.cavitus.com . Crafers. Accessed 10 Jan 2011Chea Chua S, Ping Tan C, Mirhosseini H, Ming Lai O, Long K, Sham Baharin B (2009) Optimization of ultrasound extraction condition of phospholipids from palm-pressed fiber. J Food Eng 92:403–409Chena R, Menga F, Zhang S, Liu Z (2009) Effects of ultrahigh pressure extraction conditions on yields and antioxidant activity of ginsenoside from ginseng. Sep Purif Technol 66:340–346Chivate MM, Pandit AB (1995) Quantification of cavitation intensity in fluid bulk. Ultrason Sonochem 2:19–25Da Porto C, Decorti D (2009) Ultrasound-assisted extraction coupled with under vacuum distillation of flavour compounds from spearmint (carvone-rich) plants: comparison with conventional hydrodistillation. Ultrason Sonochem 16:795–799Da Porto C, Decorti D, Kikic I (2009) Flavour compounds of Lavandula angustifolia L. to use in food manufacturing: Comparison of three different extraction methods. Food Chem 112:1072–1078Domínguez H, Núñez MJ, Lema JM (1994) Enzymatic pretreatment to enhance oil extraction from fruits and oilseeds: a review. Food Chem 49:271–286Dong J, Liu Y, Liang Z, Wanga W (2010) Investigation on ultrasound-assisted extraction of salvianolic acid B from Salvia miltiorrhiza root. Ultrason Sonochem 17:61–65Entezari MH, Kruus P (1994) Effect of frequency on sonochemical reactions. I: oxidation of iodide. Ultrason Sonochem 1:75–79Esclapez MD, Sáez V, Milán-Yáñez D, Tudela I, Louisnard O, González-García J (2010) Sonoelectrochemical treatment of water polluted with trichloroacetic acid: from sonovoltammetry to pre-pilot plant scale. Ultrason Sonochem 17:1010–1020Ferraro V, Cruz IB, Ferreira R, Malcata JFX, Pintado ME, Castro PML (2010) Valorisation of natural extracts from marine source focused on marine by-products: review. Food Res Int 43:2221–2233Fischer CH, Hart EJ, Henglein AJ (1986) Hydrogen/deuterium isotope exchange in the hydrogen deuteride-water system under the influence of ultrasound. Phys Chem 90:3059–3060Garcia-Noguera J, Weller CL, Oliveira FIP, Rodrigues S, Fernandes FAN (2010) Dual-stage sugar substitution in strawberries with a Stevia-based sweetener. Innovative Food Sci Emerg Technol 11:225–230García-Pérez JV, Cárcel JA, de la Fuente-Blanco S, Riera-Franco de Sarabia E (2006) Ultrasonic drying of foodstuff in a fluidized bed: parametric study. Ultrasonics 44:539–543García-Pérez JV, García-Alvarado MA, Carcel JA, Mulet A (2010) Extraction kinetics modeling of antioxidants from grape stalk (Vitis vinifera var. Bobal): Influence of drying conditions. J Food Eng 101:49–58González-García J, Sáez V, Tudela I, Díez-Garcia MI, Esclapez MD, Louisnard O (2010) Sonochemical treatment of water polluted by chlorinated organocompounds. A review. Water 2:28–74Handa SS, Preet S, Khanuja S, Longo G, Rakesh DD (2008) Extraction Technologies for Medicinal and Aromatic Plants. United Nations Industrial Development Organization and the International Centre for Science and High Technology, TriesteHemwimol S, Pavasant P, Shotipruk A (2006) Ultrasound-assisted extraction of anthraquinones from roots of Morinda citrifolia. Ultrason Sonochem 13:543–548Hielscher (2011) Teltow http:// www.hielscher.com . Accessed 10 Jan 2011Hu Y, Wang T, Wang M, Han S, Wan P, Fan M (2008) Extraction of isoflavonoids from Pueraria by combining ultrasound with microwave vacuum. Chem Engin Process 47:2256–2261Ince NH, Tezcanli G, Belen RK, Apikyan PG (2001) Ultrasound as a catalyzer of aqueous reaction systems: the state of the art and environmental applications. Appl Catal B 29:167–176Jadhav D, Rekha BN, Gogate PR, Rathod VK (2009) Extraction of vanillin from vanilla pods: a comparison study of conventional soxhlet and ultrasound assisted extraction. J Food Eng 93:421–426Ji J-b, Lu X-h, Cai M-q, Xu C-c (2006) Improvement of leaching process of Geniposide with ultrasound. Ultrason Sonochem 13:455–462Kanthale PM, Gogate PR, Pandit AB, Wilhelm AM (2003) Mapping of an ultrasonic horn: link primary and secondary effects of ultrasound. Ultrason Sonochem 10:331–335Karki B, Lamsal BP, Jung S, van Leeuwen JH, Pometto AL III, Grewell D, Khanal SK (2010) Enhancing protein and sugar release from defatted soy flakes using ultrasound technology. J Food Eng 96:270–278Kardos N, Luche J-L (2001) Sonochemistry of carbohydrate compounds. Carbohydr Res 332:115–131Kotronarou A, Mills G, Hoffmann MR (1991) Ultrasonic Irradiation of para-Nitrophenol in Aqueous Solution. J Phys Chem 95:3630–3638Kuijpers MWA, Kemmere MF, Keurentjes JTF (2002) Calorimetric study of the energy efficiency for ultrasound-induced radical formation. Ultrasonics 40:675–678Leighton TG (2007) What is ultrasound? Prog Biophys Mol Biol 93:3–83Leonelli C, Mason TJ (2010) Microwave and ultrasonic processing: now a realistic option for industry. Chem Eng Process 49:885–900Li H, Pordesimo L, Weiss J (2004) High intensity ultrasound-assisted extraction of oil from soybeans. Food Res Int 37:731–738Liu J, Li J-W, Tang J (2010) Ultrasonically assisted extraction of total carbohydrates from Stevia rebaudiana Bertoni and identification of extracts. Food Bioprod Process 88:215–221Lianfu Z, Zelong L (2008) Optimization and comparison of ultrasound/microwave assisted extraction (UMAE) and ultrasonic assisted extraction (UAE) of lycopene from tomatoes. Ultrason Sonochem 15:731–737Liazid A, Schwarz M, Varela RM, Palma M, Guillén DA, Brigui J, Macías FA, Barroso CG (2010) Evaluation of various extraction techniques for obtaining bioactive extracts from pine seeds. Food Bioprod Process 88:247–252Londoño-Londoño J, Rodrigues de Lima V, Lara O, Gil A, Crecsynski Pasa TB, Arango GJ, Ramirez Pineda JR (2010) Clean recovery of antioxidant flavonoids from citrus peel: optimizing an aqueous ultrasound-assisted extraction method. Food Chem 119:81–87Lou Z, Wang H, Zhang M, Wang Z (2010) Improved extraction of oil from chickpea under ultrasound in a dynamic system. J Food Eng 98:13–18Louisnard O, González-García J, Tudela I, Klima J, Sáez V, Vargas-Hernández Y (2009) FEM simulation of a sono-reactor accounting for vibrations of the boundaries. Ultrason Sonochem 16:250–259Luque de Castro MD, Priego-Capote F (2007) Analytical Applications of Ultrasound, Vol. 26, Techniques and Instrumentation in Analytical Chemistry. Elsevier Science, AmsterdamMa Y, Ye X, Hao Y, Xu G, Xu G, Liu D (2008) Ultrasound-assisted extraction of hesperidin from Penggan (Citrus reticulata) peel. Ultrason Sonochem 15:227–232Ma Y, Chen J-C, Liu Dong-Hong, Ye X-Q (2009) Simultaneous extraction of phenolic compounds of citrus peel extracts: effect of ultrasound. Ultrason Sonochem 16:57–62Makino K, Mossoba MM, Riesz P (1982) Chemical effects of ultrasound on aqueous solutions. Evidence for hydroxyl and hydrogen free radicals (.cntdot. OH and. cntdot. H) by spin trapping. J Chem Soc 104:3537–3539Margulis MA, Margulis IM (2003) Calorimetric method for measurement of acoustic power absorbed in a volume of liquid. Ultrason Sonochem 10:343–345Martin CJ, Law ANR (1983) Design of thermistor probes for measurement of ultrasound intensity distributions. Ultrasonics 21:85–90Mason TJ, Lorimer JP, Bates DM, Zhao Y (1994) Dosimetry in sonochemistry: the use of aqueous terephthalate ion as a fluorescence monitor. Ultrason Sonochem 1:91–95Meinhardt (2011) Leipzig. http://www.meinhardt-ultraschall.de . Accessed 10 Jan 2011Montalbo-Lomboy M, Khanal SK, van Leeuwen JH, Raman DR, Dunn L Jr, Grewell D Jr (2010) Ultrasonic pretreatment of corn slurry for saccharification: a comparison of batch and continuous Systems. Ultrason Sonochem 17:939–946Mulet A, Cárcel JA, Sanjuán N, Bon J (2003) New food drying technologies. Use of ultrasound. Food Sci Technol Int 9:215–221Naguleswaran S, Vasanthan T (2010) Dry milling of field pea (Pisum sativum L.) groats prior to wet fractionation influences the starch yield and purity. Food Chem 118:627–633Orozco-Solano M, Ruiz-Jiménez J, Luque de Castro MD (2010) Ultrasound-assisted extraction and derivatization of sterols and fatty alcohols from olive leaves and drupes prior to determination by gas chromatography–tandem mass spectrometry. J Chromatogr A 1217:1227–1235Patist A, Bates D (2008) Ultrasonic innovations in the food industry: from the laboratory to commercial production. Innovative Food Sci Emerg Technol 9:147–154Price GJ (1990) The use of ultrasound for the controlled degradation of polymer solutions. In: Mason TJ (ed) Advances in sonochemistry, vol 1. Jai Press, Cambridge, pp 231–287Riener J, Noci G, Cronin DA, Morgan DJ, Lyng JG (2010) A comparison of selected quality characteristics of yoghurts prepared from thermosonicated and conventionally heated milks. Food Chem 119:1108–1113Riera E, Golás Y, Blanco A, Gallego JA, Blasco M, Mulet A (2004) Mass transfer enhancement in supercritical fluids extraction by means of power ultrasound. Ultrason Sonochem 11:241–244Riera E, Blanco A, García J, Benedito J, Mulet A, Gallego-Juárez JA, Blasco M (2010) High-power ultrasonic system for the enhancement of mass transfer in supercritical CO2 extraction processes. Physics Procedia 3:141–146Roldán-Gutiérrez JM, Ruiz-Jiménez J, Luque de Castro MD (2008) Ultrasound-assisted dynamic extraction of valuable compounds from aromatic plants and flowers as compared with steam distillation and superheated liquid extraction. Talanta 75:1369–1375Romdhane M, Gourdon C (2002) Investigation in solid–liquid extraction: influence of ultrasound. Chem Eng J 87:11–19Rong L, Kojima Y, Koda S, Nomura H (2008) Simple quantification of ultrasonic intensity using aqueous solution of phenolphthalein. Ultrason Sonochem 8:11–15Sáez V, Frias-Ferrer A, Iniesta J, Gonzalez-Garcıa J, Aldaz A, Riera E (2005) Chacterization of a 20 kHz sonoreactor. Part I: analysis of mechanical effects by classical and numerical methods. Ultrason Sonochem 12:59–65Sáez V, Frias-Ferrer A, Iniesta J, Gonzalez-Garcıa J, Aldaz A, Riera E (2005) Characterization of a 20 kHz sonoreactor. Part II: analysis of chemical effects by classical and electrochemical methods. Ultrason Sonochem 12:67–72Sahena F, Zaidul ISM, Jinap S, Karim AA, Abbas KA, Norulaini NAN, Omar AKM (2009) Application of supercritical CO2 in lipid extraction–A review. J Food Eng 95:240–253Science Direct Database (2011) www.sciencedirect.com (Data of consulting: February 2011)Soria AC, Villamiel M (2010) Effect of ultrasound on the technological properties and bioactivity of food: a review. Trends Food Sci Technol 21:323–331Starmans DAJ, Nijhuis HH (1996) Extraction of secondary metabolites from plant material: a review. 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Ultrason Sonochem 3:125–130Veillet S, Tomao V, Chemat F (2010) Ultrasound assisted maceration: an original procedure for direct aromatisation of olive oil with basil. Food Chem 123:905–911Velickovic DT, Milenovic DM, Ristic MS, Veljkovic VB (2008) Ultrasonic extraction of waste solid residues from the Salvia sp. Essential oil hydrodistillation. Biochem Eng J 42:97–104Vercet A, Burgos J, Crelier S, Lopez-Buesa P (2001) Inactivation of proteases and lipases by ultrasound. Innovative Food Sci Emerg Technol 2:139–150Vilkhu K, Mawson R, Simons L, Bates D (2008) Applications and opportunities for ultrasound assisted extraction in the food industry—A review. Innovative Food Sci Emerg Technol 9:161–169Vinatoru M (2001) An overview of the ultrasonically assisted extraction of bioactive principles from herbs. 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Kaposi's Sarcoma Associated Herpes Virus (KSHV) Induced COX-2: A Key Factor in Latency, Inflammation, Angiogenesis, Cell Survival and Invasion

Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. Primary infection of human micro vascular endothelial cells (HMVEC-d) results in the establishment of latent infection and reprogramming of host genes, and cyclooxygenase-2 (COX-2) is one of the highly up-regulated genes. Our previous study suggested a role for COX-2 in the establishment and maintenance of KSHV latency. Here, we examined the role of COX-2 in the induction of ICs, GFs, angiogenesis and invasive events occurring during KSHV de novo infection of endothelial cells. A significant amount of COX-2 was detected in KS tissue sections. Telomerase-immortalized human umbilical vein endothelial cells supporting KSHV stable latency (TIVE-LTC) expressed elevated levels of functional COX-2 and microsomal PGE2 synthase (m-PGES), and secreted the predominant eicosanoid inflammatory metabolite PGE2. Infected HMVEC-d and TIVE-LTC cells secreted a variety of ICs, GFs, angiogenic factors and matrix metalloproteinases (MMPs), which were significantly abrogated by COX-2 inhibition either by chemical inhibitors or by siRNA. The ability of these factors to induce tube formation of uninfected endothelial cells was also inhibited. PGE2, secreted early during KSHV infection, profoundly increased the adhesion of uninfected endothelial cells to fibronectin by activating the small G protein Rac1. COX-2 inhibition considerably reduced KSHV latent ORF73 gene expression and survival of TIVE-LTC cells. Collectively, these studies underscore the pivotal role of KSHV induced COX-2/PGE2 in creating KS lesion like microenvironment during de novo infection. Since COX-2 plays multiple roles in KSHV latent gene expression, which themselves are powerful mediators of cytokine induction, anti-apoptosis, cell survival and viral genome maintainence, effective inhibition of COX-2 via well-characterized clinically approved COX-2 inhibitors could potentially be used in treatment to control latent KSHV infection and ameliorate KS