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LE Magazine July 1999

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Featured:

  • Protective Properties of Artichoke Leaf Extract
  • Sun Protection
  • Embryonic Stem Cell Research

Artichoke extract's antioxidative and
protective effects

Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes

Gebhardt R
Physiologisch-Chemisches Institut, University of Tubingen, Germany.
Toxicol Appl Pharmacol 1997 Jun;144(2):279-86

Primary rat hepatocyte cultures exposed to tert-butylhydroperoxide (t-BHP) or cumene hydroperoxide were used to assess the antioxidative and protective potential of water-soluble extracts of artichoke leaves. Both hydroperoxides stimulated the production of malondialdehyde (MDA), particularly when the cells were pretreated with diethylmaleate (DEM) in order to diminish the level of cellular glutathione (GSH). Addition of artichoke extracts did not affect basal MDA production, but prevented the hydroperoxide-induced increase of MDA formation in a concentration-dependent manner when presented simultaneously or prior to the peroxides. The effective concentrations (down to 0.001 mg/ml) were well below the cytotoxic levels of the extracts which started above 1 mg/ml. The protective potential assessed by the LDH leakage assay and the MTT assay closely paralleled the reduction in MDA production and largely prevented hepatocyte necrosis induced by the hydroperoxides. The artichoke extracts did not affect the cellular level of glutathione (GSH), but diminished the loss of total GSH and the cellular leakage of GSSG resulting from exposure to t-BHP. Chlorogenic acid and cynarin accounted for only part of the antioxidative principle of the extracts which was resistant against tryptic digestion, boiling, acidification, and other treatments, but was slightly sensitive to alkalinization. These results demonstrate that artichoke extracts have a marked antioxidative and protective potential. Primary hepatocyte cultures seem suitable for identifying the constituents responsible for these effects and for elucidating their possible mode of action.


Dicaffeoylquinic acids and HIV

Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: inhibition of the core catalytic domain of human immunodeficiency virus integrase

Robinson WE Jr, Cordeiro M, Abdel-Malek S, Jia Q, Chow SA, Reinecke MG, Mitchell WM
Department of Pathology, University of California, Irvine 92697-4800, USA. ewrobine@uci.edu
Mol Pharmacol 1996 Oct;50(4):846-55

Integration of a cDNA copy of the human immunodeficiency virus (HIV) genome is mediated by an HIV-1-encoded enzyme, integrase (IN), and is required for productive infection of CD4+ lymphocytes. It had been shown that 3,5-dicaffeoylquinic acid and two analogues were potent and selective inhibitors of HIV-1 IN in vitro. To determine whether the inhibition of IN by dicaffeoylquinic acids was limited to the 3,5 substitution, 3,4-, 4,5-, and 1,5-dicaffeoylquinic acids were tested for inhibition of HIV-1 replication in tissue culture and inhibition of HIV-1 IN in vitro. All of the dicaffeoylquinic acids were found to inhibit HIV-1 replication at concentrations ranging from 1 to 6 microM in T cell lines, whereas their toxic concentrations in the same cell lines were>120 microM. In addition, the compounds inhibited HIV-1 IN in vitro at submicromolar concentrations.

Molecular modeling of these ligands with the core catalytic domain of IN indicated an energetically favorable reaction, with the most potent inhibitors filling a groove within the predicted catalytic site of IN. The calculated change in internal free energy of the ligand/IN complex correlated with the ability of the compounds to inhibit HIV-1 IN in vitro. These results indicate that the dicaffeoylquinic acids as a class are potent and selective inhibitors of HIV-1 IN and form important lead comounds for HIV drug discovery.


Chlorogenic acid inhibits carcinogenic reactions

The suppression of the N-nitrosating reaction by chlorogenic acid

Kono Y, Shibata H, Kodama Y, Sawa Y
Department of Bacteriology, Faculty of Medicine, Tottori University, Japan.
Biochem J 1995 Dec 15;312 ( Pt 3):947-53

N-Nitrosation of a model aromatic amine (2,3-diamino-naphthalene) by the N-nitrosating agent produced by nitrite in acidic solution was inhibited by a polyphenol, chlorogenic acid, which is an ester of caffeic acid quinic acid. Caffeic acid also inhibited the N-nitrosation, but quinic acid did not. 1,2-Benzenediols and 3,4-dihydroxybenzoic acid had inhibitory activities. Chlorogenic acid, caffeic acid, 1,2-benzenediols and 3,4-dihydroxybenzoic acid were able to scavenge the stable free radical, 1,1-diphenyl-2-picrylhydrazyl. Chlorogenic acid was found to be nitrated by acidic nitrite. The kinetic studies and the nitration observed only by bubbling of nitric oxide plus nitrogen dioxide gases indicated that the nitrating agent was nitrogen sesquioxide. The observations showed that the mechanism by which chlorogenic acid inhibited N-nitrosation of 2,3-diamino-naphthalene is due to its ability to scavenge the nitrosating agent, nitrogen sesquioxide. Chlorogenic acid may be effective not only in protecting against oxidative damage but also in inhibiting potentially mutagenic and carcinogenic reactions in vivo.


Topical application of vitamin E and sun protection

Prevention of DNA photodamage by vitamin E compounds and sunscreens: roles of ultraviolet absorbance and cellular uptake

McVean M, Liebler DC
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, USA.
Mol Carcinog 1999 Mar;24(3):169-76

Topical application of alpha-tocopherol (alphaTH), the most prominent naturally occurring form of vitamin E, inhibits ultraviolet (UV) B-induced photocarcinogenesis and DNA photodamage in C3H mice in vivo. In this study, we compared alphaTH with other vitamin E compounds and with three commercial sunscreen compounds for their ability to inhibit DNA photodamage in C3H mouse skin in vivo. When applied in a 5% dispersion in a neutral cream vehicle, alpha-tocopherol (alphaTH), gamma-tocopherol (gammaTH), and delta-tocopherol (deltaTH) each produced a statistically significant inhibition of thymine dimer formation, whereas alpha-tocopherol acetate (alphaTAc) and alpha-tocopherol methyl ether (alphaTOMe) did not. Application of 5% dispersions of the commercial sunscreen agent octylmethoxycinnamate also inhibited dimer formation, whereas ethylhexyl salicylate and oxybenzone did not, despite their considerably greater UVB absorbances than alphaTH. To test the hypothesis that cellular uptake and distribution are necessary for optimal photoprotection by tocopherols, photoprotection was studied in mouse 308 keratinocyte cells in vitro. Preincubation of 308 cells with 1 microM alphaTH for at least 2 h before exposure to 2.5 J/m2/s UVB for 10 min significantly (P < 0.05) attenuated thymine dimer formation. Pre-incubation with 1 microM gammaTH, deltaTH, alphaTAc, or alphaTOMe for 2 h did not inhibit thymine dimer formation significantly. Uptake of alphaTH was measured after incubation with 1 microM [2H3]alphaTH (d3-alphaTH) and resulted in a time-dependent increase in alphaTH levels. Use of d3-alphaTH allowed separate, simultaneous measurement of added d3-alphaTH and unlabeled endogenous alphaTH by gas chromatography-mass spectrometry. Accumulation of 167 +/- 62 pmol d3-alphaTH/mg protein was measured within 1 h in whole-cell fractions. d3-AlphaTH in the nuclear fraction reached levels of 15 +/- 4 pmol d3-alphaTH/mg protein at 2 h. Accumulation of alphaTH in the whole cell and nuclei corresponded temporally with significant protection against DNA photodamage. The kinetics of accumulation of the three tocopherols in whole cells and in nuclei were similar. Although only alphaTH conferred significant protection compared with irradiated controls at 2 h, the differences between individual tocopherols were not statistically significant. This work suggests that incorporation of tocopherol compounds into sunscreen products confers protection against procarcinogenic DNA photodamage and that cellular uptake and distribution of tocopherol compounds is necessary for their optimal photoprotection.


Melanoma incidence and sun damage

Update on the incidence and mortality from melanoma in the United States

Hall HI, Miller DR, Rogers JD, Bewerse B
Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA.
J Am Acad Dermatol 1999 Jan;40(1):35-42

BACKGROUND: Increases in the incidence of malignant melanoma have been among the largest of all cancers in the United States. OBJECTIVE: We report updated trends in melanoma rates among the US white population. METHODS: Incidence and mortality rates were calculated for 1973 to 1994. Trends were examined with stratification by state, age, and sex, and by anatomic site, stage, and melanoma thickness at diagnosis. RESULTS: Melanoma incidence and mortality rates increased dramatically from 1973 to 1994, rising 120.5% and 38.9%, respectively. In recent years, however, rates for most age-sex groups appeared to stabilize or even decline. Male patients continued to have higher incidence and mortality rates than female patients, but for both male and female patients the largest increases by site were for the trunk. A large proportion of melanomas were detected in the local stage and with a thickness less than 0.75 mm. CONCLUSION: Prevention of sun exposure is recommended to reverse the high incidence rates of melanoma.


Sun protection awareness

Use of photoprotective measures in relation to actual exposure to solar rays

Kozarev J
Med Pregl 1998 Nov-Dec;51(11-12):555-8

OBJECTIVE: There is evidence that in spite of worldwide campaigns against excessive sun exposure, children as well as adults still spend long periods in the sun. The purpose of this study was to evaluate sun exposure in a group of doctors of different specialties and to compare their knowledge about sun protection methods with regular use of sun protection products. METHODS: 51 doctors of different specialties, volunteers, mean age 40.78, filled out questionnaires with 21 multiple choice questions about their skin type, sun exposure habits, sun protection habits and questions about meaning of the Sun Protection Factor. RESULTS: Thirty-three percent of our study participants spent more than two peak ultraviolet hours outdoors everyday, and additional 33.33% are sun exposed for longer than 5 hours, regularly. Only 39% of them utilized sunscreens. Majority of sunscreen users utilized less than 100 ml of commercial sunscreen products which is an inadequate amount for full body protection per year. Majority of study participants did not believe that sunscreens could prevent skin cancer, but 57% of them believed that these compounds can slow the process of skin aging. Meaning of the term Sun Protection Factor is not familiar to 84.3% study participants. The two most common reasons for not using sunscreens are time consuming application and high cost. CONCLUSION: Results of the presented study confirm our statement that there is bad understanding of a need for sun protection which is in correlation with deficient application of sun protective measures. It should be stressed that our study participants lack well formed sun protection habits.


Uses for pluripotent cell lines

Embryonic stem cell lines derived from human blastocysts

Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM
Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.
Science 1998 Nov 6;282(5391):1145-7

Human blastocyst-derived, pluripotent cell lines are described that have normal karyotypes, express high levels of telomerase activity, and express cell surface markers that characterize primate embryonic stem cells but do not characterize other early lineages. After undifferentiated proliferation in vitro for 4 to 5 months, these cells still maintained the developmental potential to form trophoblast and derivatives of all three embryonic germ layers, including gut epithelium (endoderm); cartilage, bone, smooth muscle, and striated muscle (mesoderm); and neural epithelium, embryonic ganglia, and stratified squamous epithelium (ectoderm). These cell lines should be useful in human developmental biology, drug discovery, and transplantation medicine.


Cell cultures reveal differentiated cell types

Derivation of pluripotent stem cells from cultured human primordial germ cells

Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD
Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Proc Natl Acad Sci US 1998 Nov 10;95(23):13726-31

Human pluripotent stem cells would be invaluable for in vitro studies of aspects of human embryogenesis. With the goal of establishing pluripotent stem cell lines, gonadal ridges and mesenteries containing primordial germ cells (PGCs, 5-9 weeks postfertilization) were cultured on mouse STO fibroblast feeder layers in the presence ofhuman recombinant leukemia inhibitory factor, human recombinant basic fibroblast growth factor, and forskolin. Initially, single PGCs in culture were visualized by alkaline phosphatase activity staining. Over a period of 7-21 days, PGCs gave rise to large multicellular colonies resembling those of mouse pluripotent stem cells termed embryonic stem and embryonic germ (EG) cells. Throughout the culture period most cells within the colonies continued to be alkaline phosphatase-positive and tested positive against a panel of five immunological markers (SSEA-1, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81) that have been used routinely to characterize embryonic stem and EG cells. The cultured cells have been continuously passaged and found to be karyotypically normal and stable. Both XX and XY cell cultures have been obtained. Immunohistochemical analysis of embryoid bodies collected from these cultures revealed a wide variety of differentiated cell types, including derivatives of all three embryonic germ layers. Based on their origin and demonstrated properties, these human PGC-derived cultures meet the criteria for pluripotent stem cells and most closely resemble EG cells.



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