E2 Alpha Research Articles

Anti-Inflammatory Activity of 1,6,7-Trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone Isolated from Cudrania tricuspidata via NF-κB, MAPK, and HO-1 Signaling Pathways in Lipopolysaccharide-Stimulated RAW 264.7 and BV2 Cells.

Neuroinflammation activated by microglia affects inflammatory pain development. This study aimed to explore the anti-inflammatory properties and mechanisms of 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone (THMX) from Cudrania tricuspidata in microglia activation-mediated inflammatory pain. In RAW 264.7 and BV2 cells, THMX has been shown to reduce lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory mediators and cytokines, including nitric oxide (NO), prostaglandin (PG) E2, interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α). THMX also decreased LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK) and the activation of p65 nuclear factor kappa B (NF-κB). Interestingly, THMX also activated heme oxygenase (HO)-1 expression. These findings suggest that THMX is a promising biologically active compound against inflammation through preventing MAPKs and NF-ĸB and activating HO-1 signaling pathways.

Efficacy of prostaglandin E2 versus prostaglandin F2 alpha assisted with narrowband-UVB in stable vitiligo

In the recent decades, prostaglandins were recommended as a new therapeutic modality of stable vitiligo with promising efficacy. Therefore, we designed the current work to compare the significance of two different subtypes of prostaglandins [prostaglandin E2 (PGE2) versus prostaglandin F2 alpha (PGF2α)], assisted with NB-UVB phototherapy, in treatment of stable vitiligo. This study was conducted on 30 patients with stable non-segmental vitiligo. Three approximately similar vitiliginous areas were chosen in each patient and assigned into 3 groups. Each group treated with intradermal injection of either PGE2 (group I), PGF2α (group II), or saline as placebo (group III) at frequency once/week for 12 weeks. Concomitantly, all groups received NB-UVB phototherapy twice weekly for 3 months. The outcomes of this study discovered that the therapeutic efficacy of intradermal injection of either PGE2 or PGF2α assisted with NB-UVB phototherapy was comparable with non-significant difference between them in spite of being significantly higher than NB-UVB alone. However, there were a significantly earlier onset of repigmentation and higher degree of satisfaction regarding areas treated with PGE2 than those treated with PGF2α. In conclusion, both PGF2α and PGE2 intradermal injection could be considered as quite simple and affordable techniques in the treatment of stable vitiligo with no reported side effects and good patient satisfaction.

The physiological and pharmacological roles of prostaglandins in hair growth.

Hair loss is a common status found among people of all ages. Since the role of hair is much more related to culture and individual identity, hair loss can have a great influence on well-being and quality of life. It is a disorder that is observed in only scalp patients with androgenetic alopecia (AGA) or alopecia areata caused by stress or immune response abnormalities. Food and Drug Administration (FDA)-approved therapeutic medicines such as finasteride, and minoxidil improve hair loss temporarily, but when they stop, they have a limitation in that hair loss occurs again. As an alternative strategy for improving hair growth, many studies reported that there is a relationship between the expression levels of prostaglandins (PGs) and hair growth. Four major PGs such as prostaglandin D2 (PGD2), prostaglandin I2 (PGI2), prostaglandin E2 (PGE2α), and prostaglandin F2 alpha (PGF2α) are spatiotemporally expressed in hair follicles and are implicated in hair loss. This review investigated the physiological roles and pharmacological interventions of the PGs in the pathogenesis of hair loss and provided these novel insights for clinical therapeutics for patients suffering from alopecia.

The Role of Prostaglandins in Different Types of Cancer

The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins associated with different types of cancer and the advances related to the potential use of them in neoplasm therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among others. Prostaglandin D2 (PGD2) seems to hinder tumor progression, while prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) seem to provide greater tumor progression and aggressiveness. However, more studies are needed to determine the role of prostaglandin I2 (PGI2) and prostaglandin J2 (PGJ2) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs (non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the prostaglandins involved in different cancer and the different targets modulated by them, as well as their role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic tools to fight cancer.

Tumor risk biomarkers and physical activity in type 2 diabetes, patients with colorectal cancer and individuals without diabetes

Biomarkers such as 8-oxo-2’deoxy-guanosine (8-oxo-dG), prostaglandin E2 alpha (PGE2 alpha), prostaglandin metabolites (PGEM) and 8-isoprostane (8-iso) may quantitatively reflect individual tumor risk including colorectal cancer (CRC) and may be useful in clinical management and prevention programs. To further clarify their role in a clinical setting we compared urinary excretion levels with regard to physical activity and other clinical and metabolic parameters in patients with longstanding (>5 years) type 2 diabetes (T2D) (moderate risk) and in those with curatively treated CRC (high risk for recurrence). Patients and methodsIn this one center case-control study 60 patients with T2D and 40 patients with CRC were compared with 40 healthy controls. Levels of physical activity were assessed in MET-hr/wk. Urinary excretion of 8-oxo-dG, PGE2 alpha, PGEM and 8-iso were determined by HPLC-ESI mass-spectrometry and ELISA, respectively. ResultsUrinary 8-oxo-dG excretion was 33.7% higher in T2D compared to controls (P=0.01), in CRC excretion was 83.6% higher (p<0.0001). There was a positive correlation with BMI (p=0.04) in all study participants. There were no significant correlations with the levels of physical activity and other clinical and metabolic parameters (HbA1c, pre-, post-prandial glucose). Urinary excretion of PGE2alpha, PGEM and 8-iso were similar in all study participants. ConclusionsThis study provides quantitative biomarker data which may be useful in management and prevention programs. One important clinical application would be the implementation of biomarker data into risk prediction models to improve accuracy. The lack of correlation with the levels of physical activity does not preclude their value in interventional settings.

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-\u03baB/COX-2/PG pathway

BackgroundPrimary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear.MethodsTo investigate the potential role of NLRP3 inflammasome activation in the pathogenesis of PD, 30 female Kunming mice without pregnancy were used for experiments. The PD mouse model was constructed by 11 days of successive co-treatment with estradiol and oxytocin. MCC950, a potent and specific small-molecule inhibitor of the NLRP3 inflammasome, was used to treat PD mice. The disease level was assessed by the writhing response and hot water tail-flick test. The levels of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) in the uterine tissues of mice were detected by ELISA. The expression levels of protein and cytokines, including NLRP3, cysteine aspartic acid-specific protease 1 (caspase-1), interleukin (IL)-1β, IL-18, nuclear factor kappa B (NF-κB) p65, phospho-NF-κB p65, and cyclooxygenase-2 (COX-2) were revealed by western blot analysis.ResultsMCC950 greatly ameliorated the writhing response induced by the combination of oxytocin and estradiol, with an increasing length of tail-flick latency. MCC950 also significantly decreased the levels of PGF2α and PGE2, and the expressions of NLRP3, caspase-1, IL-1β, IL-18, phospho-NF-κB p65, NF-κB p65, and COX-2 in the uterus.ConclusionsMCC950 markedly alleviated the pain and pathological damage in PD mice by inhibiting NLRP3 activation. The underlying mechanism may be related to hypoactive uterine inflammation via suppression of NLRP3 activation and the NF-κB/COX-2/PG pathway in uteruses of PD mice.

The oxytocin-prostaglandins pathways in the horse (Equus caballus) placenta during pregnancy, physiological parturition, and parturition with fetal membrane retention

Despite their importance in mammalian reproduction, substances in the oxytocin-prostaglandins pathways have not been investigated in the horse placenta during most of pregnancy and parturition. Therefore, we quantified placental content of oxytocin (OXT), oxytocin receptor (OXTR), and prostaglandin E2 and F2 alpha during days 90–240 of pregnancy (PREG), physiological parturition (PHYS), and parturition with fetal membrane retention (FMR) in heavy draft horses (PREG = 13, PHYS = 11, FMR = 10). We also quantified OXTR and prostaglandin endoperoxide synthase-2 (PTGS2) mRNA expression and determined the immunolocalization of OXT, OXTR, and PTGS2. For relative quantification of OXT and OXTR, we used western blotting with densitometry. To quantify the prostaglandins, we used enzyme immunoassays. For relative quantification of OXTR and PTGS2, we used RT-qPCR. For immunolocalization of OXT, OXTR, and PTGS2, we used immunohistochemistry. We found that OXT was present in cells of the allantochorion and endometrium in all groups. PTGS2 expression in the allantochorion was 14.7-fold lower in FMR than in PHYS (p = 0.007). These results suggest that OXT is synthesized in the horse placenta. As PTGS2 synthesis is induced by inflammation, they also suggest that FMR in heavy draft horses may be associated with dysregulation of inflammatory processes.

Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells

The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ERα) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ERα regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ERα in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ERα/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ERα/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co-immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ERα reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ERα binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ERα attenuated the activity of the BNIP3 promoter by binding to SP-1 or NFκB sites.

Omeprazole‐induced hypertrichosis in two children

Omeprazole significantly increases duodenal prostaglandin E2 synthesis. Prostaglandins are involved in hair growth regulation: prostaglandin E2 and prostaglandin F2 alpha stimulate hair growth, and prostaglandin D2 has an inhibitory effect. The use of omeprazole can cause acquired generalized hypertrichosis by increasing prostaglandin E2 levels.

Effects of lipoic acid supplementation on activities of cyclooxygenases and levels of prostaglandins E2 and F2 alpha metabolites, in the offspring of rats with Streptozotocin-induced diabetes

Effects of lipoic acid supplementation on activities of cyclooxygenases and levels of prostaglandins E2 and F2 alpha metabolites, in the offspring of rats with Streptozotocin-induced diabetes

Inhibitors of microsomal prostaglandin E2 synthase-1 enzyme as emerging anti-inflammatory candidates.

Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid (AA) into PGH2 that is further metabolized by terminal prostaglandin (PG) synthases into biologically active PGs, for example, prostaglandin E2 (PGE2), prostacyclin I2 (PGI2), thromboxane A2 (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 alpha (PGF2α). Among them, PGE2 is a widely distributed PG in the human body, and an important mediator of inflammatory processes. The successful modulation of this PG provides a beneficial strategy for the potential anti-inflammatory therapy. For instance, nonsteroidal anti-inflammatory agents (NSAIDs), both classical nonselective (cNSAIDs) and the selective COX-2 inhibitors (coxibs) attenuate the generation of PGH2 from AA that in turn reduces the synthesis of PGE2 and modifies the inflammatory conditions. However, the long-term use of these agents causes severe side effects due to the nonselective inhibition of other PGs, such as PGI2 and TXA2, etc. Microsomal prostaglandin E2 synthase-1 (mPGES-1), a downstream PG synthase, specifically catalyzes the biosynthesis of COX-2-derived PGE2 from PGH2, and describes itself as a valuable therapeutic target for the treatment of acute and chronic inflammatory disease conditions. Therefore, the small molecule inhibitors of mPGES-1 would serve as a beneficial anti-inflammatory therapy, with reduced side effects that are usually associated with the nonselective inhibition of PG biosynthesis.

Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

Madecassoside (MA), a pentacyclic triterpene isolated from Centella asitica (L.), is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV)-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

Editorial Comment from Dr Ishizuka to Effect of intrathecal administration of E‐series prostaglandin 1 receptor antagonist in a cyclophosphamide‐induced cystitis rat model

ganglia. J. Neurochem. 1991; 57: 167–74. 14 Hu VY, Malley S, Dattilio A et al. COX-2 and prostanoid expression in micturition pathways after cyclophosphamide-induced cystitis in the rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003; 284: R574–85. 15 Schroder A, Newgreen D, Andersson KE. Detrusor responses to prostaglandin E2 and bladder outlet obstruction in wild-type and EP1 receptor knockout mice. J. Urol. 2004; 172: 1166–70. 16 Chuang YC, Yoshimura N, Huang CC et al. Expression of E-series prostaglandin (EP) receptors and urodynamic effects of an EP4 receptor antagonist on cyclophosphamide-induced overactive bladder in rats. BJU Int. 2010; 106: 1782–7. 17 Minami T, Nishihara I, Uda R et al. Characterization of EP-receptor subtype involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice. Br. J. Pharmacol. 1994; 112: 735–40. 18 Uda R, Horiguchi S, Ito S et al. Nociceptive effects induced by intrathecal administration of prostaglandin D2, E2, or F2 alpha to conscious mice. Brain Res. 1990; 510: 26–32. 19 Malmberg AB, Rafferty MF, Yaksh TL. Antinociceptive effect of spinally delivered prostaglandin E receptor antagonist in the formalin test on the rat. Neurosci. Lett. 1994; 173: 193–6. 20 Miura A, Kawatani M, Maruyama T et al. Effect of prostaglandins on parasympathetic neurons in the rat lumbosacral spinal cord. Neuroreport 2002; 13: 1557–62.

Effect of tiopronin on prostaglandin synthesis in rabbit kidney medulla slices.

The effect of 2-mercaptopropionylglycine (tiopronin), which is widely used for the treatment of various hepatic disorders, on the generation of medullary prostaglandins (PG) E2 and F2 alpha has been examined. Tiopronin had a potent inhibitory effect on PG E2 formation. Simultaneously, PG F2 alpha production was increased. In the presence of tiopronin the net increased amount of PG F2 alpha was much smaller than the net decreased amount of PG E2 (6-20%). These results suggest that tiopronin has the potential to modulate PG E2 and F2 alpha synthesis by affecting endoperoxide E2 isomerase or endoperoxide reductase and that this effect may represent some pharmacological action of the drug.

The effect of prostaglandins on gastric parietal and non-parietal secretion in the anaesthetized rat.

The effects of prostaglandin E2 (PGE2), 16,16-dimethyl prostaglandin E2 (dmPGE2) and prostaglandin F2 alpha (PGF2 alpha) on gastric secretion have been examined in the anaesthetized rat. The prostaglandins stimulated the secretion of a non-parietal juice which was rich in Na+ and Cl- with smaller amounts of K+ and HCO3-. Doses of the prostaglandins that stimulated gastric non-parietal secretion also inhibited histamine stimulated gastric acid secretion, and thus the same rank order of potency was obtained for the prostaglandins on the two secretory mechanisms, viz. dmPGE2 greater than PGE2 greater than PGF2 alpha. During the secretion of endogenous gastric acid the secretagogue effect of the prostaglandins on non-parietal secretion was diminished, and this effect appeared to be due to the presence of intraluminal acid since it was mimicked by application of exogenous HCl to the gastric mucosal surface. Thus, the present results show that prostaglandins affect both the parietal and non-parietal secretions in the rat stomach and that these mechanisms show some interdependence.

Determination of free and conjugated oestrogens in peripheral blood plasma, feces and urine of cattle throughout pregnancy.

In order to further characterize oestrogen production and metabolism during bovine pregnancy, free (f) and conjugated (c) estrone (E1), total free and conjugated oestrogens (tfcOe) and total free oestrogens (tfOe) were determined as marker oestrogens in blood plasma respectively in urine and feces of 10 pregnant cows. For the determination of individual oestrogens blood, urine and feces samples of days 240, 200, 160, 100, 60, 30, 10 and 5 prior to parturition were pooled and the free, sulfo (sc)- and glucuconjugated (gc) forms of E1, 17 beta-estradiol (E2 beta) and 17 alpha-estradiol (E2 alpha) were obtained following differential enzyme hydrolysis and separation by HPLC; hormone assay was by established RIA-procedures. FE1 and cE1 concentration in blood plasma, tfOe in feces and tfcOe in urine showed a similar pattern. A first rise occurred between days 110 and 120 of pregnancy, an additional overproportional rise commenced at around days 230-250. Highest concentrations were measured in feces (tfOe ca. 500 ng/g 1 day a. p.), followed by urine (tfcOe ca. 3.5 ng/mosmol 2 days a. p.) and blood plasma (fE1 ca. 8 nmol/l and cE1 ca. 20 nmol/l 2 days a. p.). Determination of individual oestrogens in blood plasma revealed that fE2 beta and fE2 alpha could only be found 10 days a. p. while the conjugated forms could already be detected on days 100 and 160 a. p. With 62% E1 was the dominant oestrogen, followed by E2 alpha (37%) and E2 beta (1.0%); E1 occurred predominantly as sulfate, E2 alpha and E2 beta predominantly as glucuronide. Main metabloite in feces was fE2 alpha (56.7%), followed by fE2 beta (32%) and fE1 (11.3%); conjugated oestrogens were not detected. Main metabolite in urine was scE1 followed by gcE2 alpha and gcE2 beta. ScE2 alpha and scE2 beta were not detected or were present in small quantities only. Hormonal changes over time were highly significant. Main product of placental oestrogen synthesis is scE1, the concentrations of f and c E2 beta and E2 alpha in plasma largely result from oestrogen metabolism and enterohepatic circulation.

PROSTAGLANDINS IN HUMAN MILK

Levels of prostaglandin E2 and prostaglandin F2 alpha were measured by radioimmunoassay in aliquots of foremilk and hindmilk obtained at different stages of lactation (colostrum, transitional, and mature milk) from six healthy nursing mothers who delivered at term. Immunoreactive prostaglandin E2 and prostaglandin F2 alpha were detected in all fresh human milk samples, but not in cows' milk-based formulas. Further studies are necessary to investigate the role of these hormones in the physiologic function, the extrauterine adaptation, and the cytoprotective effect on the gastrointestinal tract in the breast-fed human infant.

Photobiomodulation of Pain and Inflammation in Microcrystalline Arthropathies: Experimental and Clinical Results

This article presents the results of laser therapy in crystal (hydroxyapatite, calcium pyrophosphate, and urates) deposition-induced arthritis in rats and the clinical applications in humans. Microcrystalline arthropathies are prevalent among geriatric patients, who are more vulnerable to the side effects of drugs. The effectiveness of laser therapy for pain relief, free of side effects, has been reported in painful conditions. Two milligrams of each of the above-mentioned crystals was injected in both joints of the back limbs in three groups of rats; these groups were then treated with laser irradiation. Three other groups received no treatment after the injections. We determined the plasmatic levels of inflammatory markers (fibrinogen, prostaglandin E2, and TNF(alpha)), tissues (prostaglandin E(2)) and conducted anatomopathological studies. Twenty-five patients with acute gout arthritis were randomized into two groups and treated over 5 days: group A, diclofenac 75 mg orally, twice a day; and group B, laser irradiation once a day. Forty-nine patients with knee chronic pyrophosphate arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. Thirty patients with shoulder chronic hydroxyapatite arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. Fibrinogen, prostaglandin E(2), and TNF(alpha) concentrations in the rats injected with crystals and treated with laser decreased significantly as compared with the groups injected with crystals without treatment. Both laser therapy and diclofenac achieved rapid pain relief in patients with acute gouty arthritis without significant differences in efficacy. Laser therapy was more effective than diclofenac in patients with chronic pyrophosphate arthropathy and in patients with chronic apatite deposition disease. Laser therapy represents an effective treatment in the therapeutic arsenal of microcrystalline arthropathies.

Dietary Lutein/Zeaxanthin Decreases Ultraviolet B-Induced Epidermal Hyperproliferation and Acute Inflammation in Hairless Mice

Lutein and zeaxanthin are carotenoids found in green leafy vegetables with interesting antioxidant properties. They are present in high concentrations in the fovea centralis of the human retina and their role in the prevention of age-related macula degeneration has been reported. We have investigated the effect of orally administered lutein and zeaxanthin in the cutaneous response to ultraviolet B irradiation. Female hairless SKh-1 mice receiving 0.4% and 0.04% lutein plus zeaxanthin-enriched diet for 2 wk were exposed to single doses of ultraviolet B radiation. Skin biopsies were taken at 24 and 48 h after irradiation and analyzed for the presence of apoptotic cells, proliferating cells, and expression of proliferating cell nuclear antigen. Our results show a clear ultraviolet-induced dose-dependent inflammatory response. Orally administered 0.4% lutein and zeaxanthin decreased significantly the edematous cutaneous response (p<0.01) as determined by the reduction of the UVB-induced increase of ear bifold thickening. Additionally, dietary carotenoids were efficient in reducing the ultraviolet B-induced increases in the percentage of proliferating cell nuclear antigen (p<0.05), bromodeoxyuridine (p<0.05), and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling-positive cells (p<0.01). These data demonstrate that oral supplementation of lutein and zeaxanthin diminishes the effects of ultraviolet B irradiation by reducing acute inflammatory responses and ultraviolet-induced hyperproliferative rebound.

Prostaglandin-independent effects of aspirin on cell cycle and putrescine synthesis in human colon carcinoma cells.

Aspirin consumption has been reported to be able to reduce colorectal cancer risk in humans and in animal models of colon carcinogenesis. Although the mechanism involved in such an effect is not yet clear, both prostaglandin-dependent and -independent effects have been proposed. Using HT-29 Glc(-/+)cells, which originate from a human colon adenocarcinoma, we demonstrated in this study a dose-dependent effect of millimolar concentration of aspirin on cell growth that was concomitant with a rapid accumulation of the cells in the G0/G1 phase, followed by an accumulation in the G2/M phase and by a minor increase in the proportion of cells undergoing nuclear condensation. Cell membrane integrity and cell release into the culture medium were not affected by this treatment. The aspirin effects were apparently unrelated to prostaglandin biosynthesis inhibition, since although these cells were found to express high levels of cyclooxygenase 1 (COX-1) and low levels of COX-2 proteins, they did not produce any measurable net amounts of prostaglandins, based on both utilization of radiolabelled arachidonic acid and the radioimmunoassay of prostaglandins E2 and F2 alpha. In contrast, we identified polyamine biosynthesis as a cellular target of aspirin, since the treatment of HT-29 Glc(-/+) cells with aspirin reduced the flux of L-ornithine through ornithine decarboxylase, an effect that could not be explained by an acute action of the drug on the ornithine decarboxylase catalytic activity. Since polyamine biosynthesis is strictly necessary for HT-29 cell growth, our data suggest that reduced flux through ornithine decarboxylase may participate in the antiproliferative activity of aspirin towards colonic tumoral cells. It is concluded that in HT-29 Glc(-/+) cells that are not functional for prostaglandin production, aspirin can affect cell growth, cell cycle, and polyamine biosynthesis without affecting cell membrane integrity.