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1.  A SIMPLE AND RAPID METHOD FOR SIMULTANEOUS ESTIMATION OF GLYCYRRHETINIC ACID AND PIPERINE BY HPTLC IN A HERBOMINERAL FORMULATION 
Many of the traditional herbal formulations contain extracts of Piper longum and Glycyrrhiza glabra, piperine and glycyrrhetinic acid respectively, being active constituents of these two herbs. An attempt has been made to develop a simple, precise, rapid, and cost-effective high-performance thin-layer chromatographic (HPTLC) method for simultaneous estimation of these in a herbomineral formulation (Efiplus® Capsules). Precoated silica gel 60 F254 plates with toluene-ethyl acetate-glacial acetic acid 12.5:7.5:0.5, as mobile phase were used in chromatographic determinations. The plates were scanned and the compounds were quantified at their wavelengths of maximum absorption of 260 and 331 nm for glycyrrhetinic acid and piperine respectively. The respective RF, values of glycyrrhetinic acid and piperine were 0.51 and 0.55. Under these experimental conditions linearity was observed between 0.8-2.6 μg/ spot for glycyrrhetinic acid and between 10-50 ng/ spot for piperine and average recovery was 96.25% for glycyrrhetinic acid and 98.55% for piperine.
PMCID: PMC3255427  PMID: 22247845
HPTLC; glycyrrhetinic acid; piperine; herbomineral formulation
2.  Eczema 
Clinical Evidence  2011;2011:1716.
Introduction
Eczema, as defined by the World Allergy Organization (WAO) revised nomenclature in 2003, affects 15% to 20% of school children and 2% to 5% of adults worldwide. About 50% of people with eczema demonstrate atopy, with specific immunoglobulin E responses to allergens.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of topical medical treatments, and dietary interventions in adults and children with established eczema? What are the effects of breastfeeding, reducing allergens, or dietary interventions for primary prevention of eczema in predisposed infants? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 54 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: breastfeeding, controlling house dust mites, corticosteroids, dietary exclusion of eggs or cow's milk, elementary diets, emollients, essential fatty oils, few-foods diet, multivitamins, pimecrolimus, probiotics, pyridoxine, reducing maternal dietary allergens, tacrolimus, vitamin E, and zinc supplements.
Key Points
Eczema, as defined by the World Allergy Organization (WAO) revised nomenclature in 2003, affects 15% to 20% of school children worldwide and 2% to 5% of adults. Only about 50% of people with eczema demonstrate allergic sensitisation. Remission occurs in two-thirds of children by the age of 15 years, but relapses may occur later.
Emollients are generally considered to be effective for treating the symptoms of eczema. However, the few small short-term RCTs that have been done so far do not confirm this. Sufficiently powered long-term RCTs are needed to clarify the role of emollients in the treatment of eczema.
Corticosteroids improve clearance of lesions and decrease relapse rates compared with placebo in adults and children with eczema, although we don't know which is the most effective corticosteroid or the most effective dosing regimen. Topical corticosteroids seem to have few adverse effects when used intermittently, but if they are of potent or very potent strength, they may cause burning, skin thinning, and telangiectasia, especially in children.
The calcineurin inhibitors pimecrolimus and tacrolimus improve clearance of lesions compared with placebo and may have a role in people in whom corticosteroids are contraindicated. They also seem suitable for topical use in body areas where the skin is particularly thin, such as the face.
CAUTION: An association has been suggested between pimecrolimus and tacrolimus and skin cancer in animal models. Although this association has not been confirmed in humans, calcineurin inhibitors should be used only when other treatments have failed.
We don't know whether vitamin E or multivitamins reduce symptoms in adults with eczema or whether pyridoxine, zinc supplementation, exclusion diets, or elemental diets are effective in children with eczema, as there are insufficient good-quality studies. Probiotics do not seem to reduce symptoms in children with established eczema. Essential fatty acids, such as evening primrose oil, blackcurrant seed oil, or fish oil, do not seem to reduce symptoms in people with eczema.
We don't know whether control of house dust mites or maternal dietary restriction can prevent the development of eczema in children. Observational data suggest that exclusive breastfeeding for at least 3 months does not reduce eczema risk and there is no evidence to suggest that exclusive breastfeeding alleviates eczema symptoms, unless a child is allergic to cow's milk protein.Introduction of probiotics in the last trimester of pregnancy and during breastfeeding may reduce the risk of eczema in the baby, although it remains unclear whether both antenatal and postnatal supplementation together yields the strongest protective effect. It is equally unclear which strains of probiotics are most effective.
PMCID: PMC3217753  PMID: 21609512
3.  Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11) 
Active components of complementary/alternative medicines and natural supplements are often anionic compounds and flavonoids. As such, organic anion transporters (OATs) may play a key role in their pharmacokinetic and pharmacological profiles, and represent sites for adverse drug-drug interactions. Therefore, we assessed the inhibitory effects of nine natural products, including flavonoids (catechin and epicatechin), chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid), phenolic acids (ginkgolic acids (13 : 0), (15 : 1), and (17 : 1)), and the organic acids ursolic acid and 18β-glycyrrhetinic acid, on the transport activity of the human OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11). Four compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acid (17 : 1), and 18β-glycyrrhetinic acid, significantly inhibited hOAT1-mediated transport (50 μM inhibitor versus 1 μM substrate). Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions. Only catechin inhibited hOAT4. Dose-dependency studies were conducted for 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid on hOAT1, and IC50 values were estimated as 1.2 ± 0.4 μM and 2.7 ± 0.2 μM, respectively. These data suggest that 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid may cause significant hOAT1-mediated DDIs in vivo; potential should be considered for safety issues during use and in future drug development.
doi:10.1155/2013/612527
PMCID: PMC3618943  PMID: 23573138
4.  Glycyrrhizin Attenuates MPTP Neurotoxicity in Mouse and MPP+-Induced Cell Death in PC12 Cells 
The present study examined the inhibitory effect of licorice compounds glycyrrhizin and a metabolite 18β-glycyrrhetinic acid on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and on the 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in differentiated PC12 cells. MPTP treatment increased the activities of total superoxide dismutase, catalase and glutathione peroxidase and the levels of malondialdehyde and carbonyls in the brain compared to control mouse brain. Co-administration of glycyrrhizin (16.8 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. In vitro assay, licorice compounds attenuated the MPP+-induced cell death and caspase-3 activation in PC12 cells. Glycyrrhizin up to 100µM significantly attenuated the toxicity of MPP+. Meanwhile, 18β-glycyrrhetinic acid showed a maximum inhibitory effect at 10µM; beyond this concentration the inhibitory effect declined. Glycyrrhizin and 18β-glycyrrhetinic acid attenuated the hydrogen peroxide- or nitrogen species-induced cell death. Results from this study indicate that glycyrrhizin may attenuate brain tissue damage in mice treated with MPTP through inhibitory effect on oxidative tissue damage. Glycyrrhizin and 18β-glycyrrhetinic acid may reduce the MPP+ toxicity in PC12 cells by suppressing caspase-3 activation. The effect seems to be ascribed to the antioxidant effect.
doi:10.4196/kjpp.2008.12.2.65
PMCID: PMC2817536  PMID: 20157396
Glycyrrhizin; MPTP; MPP+; Brain tissue damage; Cell death; Inhibitory effect
5.  A Randomised Controlled Trial of Ion-Exchange Water Softeners for the Treatment of Eczema in Children 
PLoS Medicine  2011;8(2):e1000395.
In a randomized trial evaluating the effect of installation of ion-exchange water softeners in the households of children with eczema, the researchers found no evidence of improvement in eczema severity as compared to usual care in the study population.
Background
Epidemiological studies and anecdotal reports suggest a possible link between household use of hard water and atopic eczema. We sought to test whether installation of an ion-exchange water softener in the home can improve eczema in children.
Methods and Findings
This was an observer-blind randomised trial involving 336 children (aged 6 months to 16 years) with moderate/severe atopic eczema. All lived in hard water areas (≥200 mg/l calcium carbonate). Participants were randomised to either installation of an ion-exchange water softener plus usual eczema care, or usual eczema care alone. The primary outcome was change in eczema severity (Six Area Six Sign Atopic Dermatitis Score, SASSAD) at 12 weeks, measured by research nurses who were blinded to treatment allocation. Analysis was based on the intent-to-treat population. Eczema severity improved for both groups during the trial. The mean change in SASSAD at 12 weeks was −5.0 (20% improvement) for the water softener group and −5.7 (22% improvement) for the usual care group (mean difference 0.66, 95% confidence interval −1.37 to 2.69, p = 0.53). No between-group differences were noted in the use of topical corticosteroids or calcineurin inhibitors.
Conclusions
Water softeners provided no additional benefit to usual care in this study population. Small but statistically significant differences were found in some secondary outcomes as reported by parents, but it is likely that such improvements were the result of response bias, since participants were aware of their treatment allocation. A detailed report for this trial is also available at http://www.hta.ac.uk.
Trial registration
Current Controlled Trials ISRCTN71423189
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Eczema (sometimes referred to as atopic dermatitis) is a chronic, inflammatory skin condition that affects about 20% of school children in developed countries. Eczema is often associated with other conditions, such as asthma, hay-fever and food allergy and can cause intractable itching leading to thickened skin, bleeding, secondary infection, sleep loss, poor concentration, and psychological distress. Current topical treatments for eczema have side effects, for example, topical corticosteroids may cause skin thinning and the long term safety of topical tacrolimus and pimecrolimus has yet to be determined. Therefore, there is a lot of interest in exploring the benefits of non-pharmacological treatments that have no apparent side effects.
Water hardness (≥200 mg/l calcium carbonate) has become a recent focus of attention.
Why Was This Study Done?
In addition to some epidemiological evidence linking increased water hardness with increased eczema prevalence, there have been widespread anecdotal reports of improvement in the skin of children with eczema when the family has moved from a hard to a soft water area. In addition, some patients report how their eczema symptoms have rapidly improved following the installation of a water softener. However, to date there have been no relevant published trials evaluating the potential benefit of water softeners for eczema. Given the lack of evidence, the high public interest in their potential benefit and the low risk of adverse effects, the researcher conducted a study to assess whether the installation of an ion-exchange water softener reduces the severity of eczema in children with moderate to severe eczema.
What Did the Researchers Do and Find?
The researchers did a pilot study that showed that it was not possible to blind participants to their treatment allocation using real and “dummy” water softener units because the softened water produced more soap suds. So the researchers conducted an observer-blind randomised controlled trial in which they used trained research nurses to conduct an objective assessment of every participant's skin. The researchers recruited 336 children who all lived in hard water areas in England. Eligible children were aged 6 months to 16 years who had a diagnosis of eczema (in line with the UK working party's diagnostic criteria) and an eczema severity score of 10 or over. Participants were randomised to either installation of an ion-exchange water softener plus usual eczema care, or usual eczema care alone. Trained research nurses examined each child's skin at baseline and at 6, 12, and 16 weeks to record changes in eczema severity. The researchers also analysed any changes in symptoms over the study period such as, sleep loss and itchiness, the amount of topical corticosteroid/calcineurin inhibitors used, the Dermatitis Family Impact questionnaire and the health related Quality of Life (children's version).
Although both treatment groups improved in disease severity during the course of the trial, the researchers found no difference between the treatment groups in the main outcome—eczema severity. Similar finding were found for night movement (scratching) and the use of topical medications (creams/ointments applied to the skin), both of which were blinded to intervention status. Nevertheless, parents in the trial did report small health benefits, and just over 50% chose to buy the water softener at the end of the trial because of perceived improvements in the eczema and the wider benefits of water softeners. It is unclear how much of this effect can be explained by prior belief in the effectiveness of the water softeners for the treatment of eczema.
What Do These Findings Mean?
The results of this study suggest that water softeners provide no additional clinical benefit to usual care in children with eczema so the use of ion-exchange water softeners for the treatment of moderate to severe eczema in children should not be recommended. However, it is up to each family to decide whether or not the wider benefits of installing a water softener in their home are sufficient to consider buying one.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000395.
The UK's NHS presents information on eczema for patients and families
MedlinePlus gives information for patients, families, and caregivers on eczema and other similar conditions
The National Eczema Society in the UK provides information and a helpline for eczema patients, families, and caregivers
Medinfo provides information for eczema patients
Wikipedia has more information about water softening (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000395
PMCID: PMC3039684  PMID: 21358807
6.  Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure  
PLoS Medicine  2008;5(6):e131.
Background
Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.
Methods and Findings
We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.
Conclusions
We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.
In two independent cohorts of children, Hans Bisgaard and colleagues show an association between mutations in the filaggrin gene (FLG) and ownership of cats, but not dogs, with development of eczema.
Editors' Summary
Background.
Eczema is a skin condition characterized by dry, red, and itchy patches on the skin. Eczema is associated with asthma and allergy, though allergy rarely plays a role in development or severity of eczema. Eczema usually begins during infancy, typically on the face, scalp, neck, extensor sides of the forearms, and legs. Up to one in five infants develops eczema, but in more than half of them, the condition improves or disappears completely before they are 15 years old. If eczema persists into adulthood, it usually affects the face and the skin inside the knees and elbows. There is no cure for eczema but it can be controlled by avoiding anything that makes its symptoms worse. These triggers include irritants such as wool, strong soaps, perfumes, and dry environments. A good skin-care routine and frequent moisturizing can also help to keep eczema under control, but in many cases, corticosteroid creams and ointments may be necessary to reduce inflammation.
Why Was This Study Done?
Eczema tends to run in families. This suggests that eczema is caused by genetic factors as well as by environmental factors. Recently, researchers discovered that two common “loss-of-function” variants in the gene encoding filaggrin (FLG) predispose people to eczema. People who inherit one or two defective genes make no filaggrin, a protein that normally forms a physical barrier in the skin that protects the body from potentially harmful substances in the environment. Might the weakening of this barrier in filaggrin-deficient individuals affect their responses to environmental substances to which the skin is exposed? In this study, the researchers test this potential explanation for how genetic and environmental factors (in particular, exposure to pets) might interact to determine an individual's chances of developing eczema.
What Did the Researchers Do and Find?
To test their hypothesis, the researchers studied two independent groups of infants during their first year of life—a high-risk group consisting of infants born in Copenhagen, Denmark to mothers with asthma and a group of infants born to women from the general population in Manchester, United Kingdom. The researchers determined which FLG variants each child had inherited and classified those with either one or two defective copies of FLG as having an FLG mutation. They determined pet exposure in early life by asking whether a dog or a cat was living in the parental home when the child was born (“pet ownership”) and then analyzed how these genetic and environmental factors affected the age of onset of eczema. In both groups, children with FLG mutations were twice as likely to develop eczema during the first year of life as children without FLG mutations. For children without FLG mutations, cat ownership at birth had no effect on eczema risk but for children with FLG mutations, cat ownership at birth (but not dog ownership) further increased the risk of developing eczema.
What Do These Findings Mean?
These findings show that FLG mutations and cat ownership at birth interact to determine the chances of a child developing eczema during the first year of life. They provide support, therefore, for the researchers' suggestion that the weakening of the skin's protective barrier that is caused by filaggrin deficiency increases the child's susceptibility to factors associated with cat exposure. Only a small number of children in this study carried FLG mutations and were exposed to cats from birth, so these findings need confirming in independent studies. In addition, it is still not clear how exposure to cats drives the development of eczema. Allergy was not the mechanism as the FLG-deficient children exposed to cat and who developed eczema did not develop cat-specific immunoglobin E antibodies. Nevertheless, these findings suggest that, to reduce their risk of developing eczema, filaggrin-deficient individuals should avoid cats (but not dogs) during the first few months of life.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050131.
The MedlinePlus Encyclopedia has a page on eczema (in English and Spanish); links to further information are provided by MedlinePlus
EczemaNet is a comprehensive online information resource about eczema provided by the American Academy of Dermatologists
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides information on eczema
The UK National Health Service Direct health encyclopedia provides information for patients on eczema (in several languages)
The Copenhagen Studies on Asthma in Childhood (COPSAC) and Manchester Asthma and Allergy Study (MAAS) Web sites provide more information about the children involved in this research
doi:10.1371/journal.pmed.0050131
PMCID: PMC2504043  PMID: 18578563
7.  Outcomes in patients with nonerosive reflux disease treated with a proton pump inhibitor and alginic acid ± glycyrrhetinic acid and anthocyanosides 
Background
The purpose of this study was to compare the efficacy of alginic acid alone versus alginic acid combined with low doses of pure glycyrrhetinic acid and bilberry anthocyanosides as an addon to conventional proton pump inhibitor therapy in relieving symptoms associated with nonerosive reflux disease.
Methods
This prospective, randomized, 8-week, open-label trial was conducted at two centers. Sixty-three patients with persistent symptoms of gastroesophageal reflux disease and normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A (n = 31) were treated with pantoprazole and a formula (Mirgeal®) containing alginic acid and low doses of pure glycyrrhetinic acid + standardized Vaccinium myrtillus extract for 4 weeks, then crossed over to the multi-ingredient formula for a further 4 weeks. Patients in group B (n = 32) were treated pantoprazole and alginic acid alone twice daily, then crossed over to alginic acid twice daily for a further 4 weeks. Efficacy was assessed by medical evaluation of a symptom relief score, estimated using a visual analog scale (0–10). Side effects, tolerability, and compliance were also assessed.
Results
Of the 63 patients enrolled in the study, 58 (29 in group A and 29 in group B) completed the 8-week trial. The baseline characteristics were comparable between the two groups. During the study, significant differences were recorded in symptom scores for both groups. In group A, symptoms of chest pain, heartburn, and abdominal swelling were less serious than in group B. Treatment A was better tolerated, did not induce hypertension, and had fewer side effects than treatment B. No significant differences in compliance were found between the two groups.
Conclusion
Use of low doses of pure glycyrrhetinic acid + bilberry anthocyanosides, together with alginic acid as addon therapy, substantially improves symptoms in patients with nonerosive reflux disease without increasing side effects or worsening tolerability or compliance.
doi:10.2147/CEG.S42512
PMCID: PMC3615700  PMID: 23569394
proton pump inhibitors; alginic acid; glycyrrhetinic acid; anthocyanosides; nonerosive reflux disease; gastroesophageal reflux disease
8.  Structure-Dependent Inhibition of Bladder and Pancreatic Cancer Cell Growth by 2-Substituted Glycyrrhetinic and Ursolic Acid Derivatives 
Derivatives of oleanolic acid, ursolic acid and glycyrrhetinic acid substituted with electron withdrawing groups at the 2-position in the A-ring which also contains a 1-en-3-one structure are potent inhibitors of cancer cell growth. In this study, we have compared the effects of several 2-substituted analogs of triterpenoid acid methyl esters derived from ursolic and glycyrrhetinic acid on proliferation of KU7 and 253JB-V bladder and Panc-1 and Panc-28 pancreatic cancer cells. The results show that the 2-cyano and 2-trifluoromethyl derivatives were the most active compounds. The glycyrrhetinic acid derivatives with the rearranged C-ring containing the 9(11)-en-12-one structure were generally more active than the corresponding 12-en-11-one isomers. However, differences in growth inhibitory IC50 values were highly variable and dependent on the 2- substitutent (CN vs. CF3) and cancer cell context.
doi:10.1016/j.bmcl.2008.03.031
PMCID: PMC2408873  PMID: 18359628
glycyrrhetinate analogs; growth inhibition; bladder cancer; pancreatic cancer
9.  Eczema (atopic) 
Clinical Evidence  2006;2006:1716.
Introduction
Atopic eczema affects 15-20% of schoolchildren worldwide and 2-10% of adults. Only about 60% of people with eczema demonstrate atopy, with specific immunoglobulin E responses to allergens.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of self-care treatments, topical medical treatments, and dietary interventions in adults and children with established atopic eczema? What are the effects of breast feeding as a primary preventive intervention in predisposed infants? What are the effects of reducing allergens as a primary preventive intervention in predisposed infants? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: breast feeding, controlling house dust mites, corticosteroids, dietary exclusion of eggs or cows' milk, elemental diets, emollients, essential fatty oils, few-foods diet, multivitamins, pimecrolimus, probiotics, pyridoxine, reducing maternal dietary allergens, tacrolimus, vitamin E, and zinc supplements.
Key Points
Atopic eczema affects 15-20% of schoolchildren worldwide and 2-10% of adults. Only about 60% of people with eczema demonstrate atopy, with specific immunoglobulin E responses to allergens. Remission occurs in two thirds of children by the age of 15 years, but relapses may occur later.
There is a consensus that emollients are effective for treating the symptoms of atopic eczema, although little high quality research has been done to confirm this.
Corticosteroids improve clearance of lesions and decrease relapse rates compared with placebo, although we don't know which is the most effective corticosteroid or dosing regimen. Topical corticosteroids seem to have few adverse effects, but may cause burning, skin thinning and telangiectasia, especially in children.
Pimecrolimus and tacrolimus improve clearance of lesions compared with placebo and may have a role in people with a high risk of corticosteroid adverse effects.
CAUTION: An association has been suggested between pimecrolimus and tacrolimus and skin cancer. They should be used only where other treatments have failed.
We don't know whether vitamin E, pyridoxine, zinc supplementation, exclusion or elemental diets or probiotics reduce symptoms in atopic eczema, as there are insufficient good quality studies. Essential fatty acids such as evening primrose oil, blackcurrant seed oil or fish oil do not seem to reduce symptoms in atopic eczema.
We don't know whether prolonged breast feeding, reducing maternal dietary allergens, or control of house dust mites, can prevent the development of atopic eczema in children. Early introduction of probiotics in the last trimester of pregnancy and during breastfeeding may reduce the risk of atopic eczema in the baby.
PMCID: PMC2907628
10.  Factors accounting for the association between anxiety and depression, and eczema: the Hordaland health study (HUSK) 
BMC Dermatology  2010;10:3.
Background
The association between anxiety and depression, and eczema is well known in the literature, but factors underlying this association remain unclear. Low levels of omega-3 fatty acids and female gender have been found to be associated with both depression and eczema. Somatization and health anxiety are known to be associated with anxiety and depression, further, somatization symptoms and health anxiety have also been found in several dermatological conditions. Accordingly, omega-3 fatty acid supplement, female gender, somatization and health anxiety are possible contributing factors in the association between anxiety and depression, and eczema. The aim of the study is to examine the relevance of proposed contributing factors for the association between anxiety and depression, and eczema, including, omega-3 fatty acid supplement, female gender, health anxiety and somatization.
Methods
Anxiety and depression was measured in the general population (n = 15715) employing the Hospital Anxiety and Depression Scale (HADS). Information on eczema, female gender, omega-3 fatty acid supplement, health anxiety and somatization was obtained by self-report.
Results
Somatization and health anxiety accounted for more than half of the association between anxiety/depression, and eczema, while the other factors examined were of minor relevance for the association of interest.
Conclusions
We found no support for female gender and omega-3 fatty acid supplement as contributing factors in the association between anxiety/depression, and eczema. Somatization and health anxiety accounted for about half of the association between anxiety/depression, and eczema, somatization contributed most. The association between anxiety/depression, and eczema was insignificant after adjustment for somatization and health anxiety. Biological mechanisms underlying the mediating effect of somatization are yet to be revealed.
doi:10.1186/1471-5945-10-3
PMCID: PMC2876073  PMID: 20412596
11.  Screening of gap junction antagonists on dye coupling in the rabbit retina 
Visual neuroscience  2007;24(4):609-618.
Many cell types in the retina are coupled via gap junctions and so there is a pressing need for a potent and reversible gap junction antagonist. We screened a series of potential gap junction antagonists by evaluating their effects on dye coupling in the network of A-type horizontal cells. We evaluated the following compounds: meclofenamic acid (MFA), mefloquine, 2-aminoethyldiphenyl borate (2-APB), 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid (18-β-GA), retinoic acid, flufenamic acid, niflumic acid, and carbenoxolone. The efficacy of each drug was determined by measuring the diffusion coefficient for Neurobiotin (Mills & Massey, 1998). MFA, 18-β-GA, 2-APB and mefloquine were the most effective antagonists, completely eliminating A-type horizontal cell coupling at a concentration of 200 μM. Niflumic acid, flufenamic acid, and carbenoxolone were less potent. Additionally, carbenoxolone was difficult to wash out and also may be harmful, as the retina became opaque and swollen. MFA, 18-β-GA, 2-APB and mefloquine also blocked coupling in B-type horizontal cells and AII amacrine cells. Because these cell types express different connexins, this suggests that the antagonists were relatively non-selective across several different types of gap junction. It should be emphasized that MFA was water-soluble and its effects on dye coupling were easily reversible. In contrast, the other gap junction antagonists, except carbenoxolone, required DMSO to make stock solutions and were difficult to wash out of the preparation at the doses required to block coupling in A-type HCs. The combination of potency, water solubility and reversibility suggest that MFA may be a useful compound to manipulate gap junction coupling.
doi:10.1017/S0952523807070472
PMCID: PMC2213422  PMID: 17711600
Horizontal cells; Retina; Gap junction antagonist
12.  Effects of a Non-Conservative Sequence on the Properties of β-glucuronidase from Aspergillus terreus Li-20 
PLoS ONE  2012;7(2):e30998.
We cloned the β-glucuronidase gene (AtGUS) from Aspergillus terreus Li-20 encoding 657 amino acids (aa), which can transform glycyrrhizin into glycyrrhetinic acid monoglucuronide (GAMG) and glycyrrhetinic acid (GA). Based on sequence alignment, the C-terminal non-conservative sequence showed low identity with those of other species; thus, the partial sequence AtGUS(-3t) (1–592 aa) was amplified to determine the effects of the non-conservative sequence on the enzymatic properties. AtGUS and AtGUS(-3t) were expressed in E. coli BL21, producing AtGUS-E and AtGUS(-3t)-E, respectively. At the similar optimum temperature (55°C) and pH (AtGUS-E, 6.6; AtGUS(-3t)-E, 7.0) conditions, the thermal stability of AtGUS(-3t)-E was enhanced at 65°C, and the metal ions Co2+, Ca2+ and Ni2+ showed opposite effects on AtGUS-E and AtGUS(-3t)-E, respectively. Furthermore, Km of AtGUS(-3t)-E (1.95 mM) was just nearly one-seventh that of AtGUS-E (12.9 mM), whereas the catalytic efficiency of AtGUS(-3t)-E was 3.2 fold higher than that of AtGUS-E (7.16 vs. 2.24 mM s−1), revealing that the truncation of non-conservative sequence can significantly improve the catalytic efficiency of AtGUS. Conformational analysis illustrated significant difference in the secondary structure between AtGUS-E and AtGUS(-3t)-E by circular dichroism (CD). The results showed that the truncation of the non-conservative sequence could preferably alter and influence the stability and catalytic efficiency of enzyme.
doi:10.1371/journal.pone.0030998
PMCID: PMC3274521  PMID: 22347419
13.  Fluid Shear-Induced ATP Secretion Mediates Prostaglandin Release in MC3T3-E1 Osteoblasts 
ATP is rapidly released from osteoblasts in response to mechanical load. We examined the mechanisms involved in this release and established that shear-induced ATP release was mediated through vesicular fusion and was dependent on Ca2+ entry into the cell via L-type voltage-sensitive Ca2+ channels. Degradation of secreted ATP by apyrase prevented shear-induced PGE2 release.
Introduction
Fluid shear induces a rapid rise in intracellular calcium ([Ca2+]i) in osteoblasts that mediates many of the cellular responses associated with mechanotransduction in bone. A potential mechanism for this increase in [Ca2+]i is the activation of purinergic (P2) receptors resulting from shear-induced extracellular release of ATP. This study was designed to determine the effects of fluid shear on ATP release and the possible mechanisms associated with this release.
Methods
MC3T3-E1 preosteoblasts were plated on type I collagen, allowed to proliferate to 90% confluency, then subjected to 12 dynes/cm2 laminar fluid flow using a parallel plate flow chamber. ATP release into the flow media was measured using a luciferin/luciferase assay. Inhibitors of channels, gap junctional intercellular communication (GJIC) and vesicular formation were added prior to shear and maintained in the flow medium for the duration of the experiment.
Results and Conclusions
Fluid shear produced a transient increase in ATP release compared to static MC3T3-E1 cells (59.8±15.7nM vs. 6.2±1.8nM, respectively), peaking within 1 min of onset. Inhibition of calcium entry through the L-type voltage-sensitive Ca2+ channel (L-VSCC) with nifedipine or verapamil significantly attenuated shear-induced ATP release. Channel inhibition had no effect on basal ATP release in static cells. Ca2+ -dependent ATP release in response to shear appeared to result from vesicular release, and not through gap hemichannels, since vesicle disruption with N-ethylmaleimide, brefeldin A, or monensin prevented increases in flow-induced ATP release, whereas inhibition of gap hemichannels with either 18α-glycyrrhetinic acid or 18β-glycyrrhetinic acid did not. Degradation of extracellular ATP with apyrase prevented shear-induced increases in PGE2 release. These data suggest a time line of mechanotransduction wherein fluid shear activates L-VSCC's to promote Ca2+ entry that, in turn, stimulates vesicular ATP release. Further, these data suggest that P2 receptor activation by secreted ATP mediates flow-induced prostaglandin release.
doi:10.1359/JBMR.041009
PMCID: PMC2929123  PMID: 15619668
ATP release; mechanotransduction; Ca2+ signaling; osteoblasts; fluid shear
14.  Synthesis of Glycyrrhetinic Acid-Modified Chitosan 5-Fluorouracil Nanoparticles and Its Inhibition of Liver Cancer Characteristics in Vitro and in Vivo 
Marine Drugs  2013;11(9):3517-3536.
Nanoparticle drug delivery (NDDS) is a novel system in which the drugs are delivered to the site of action by small particles in the nanometer range. Natural or synthetic polymers are used as vectors in NDDS, as they provide targeted, sustained release and biodegradability. Here, we used the chitosan and hepatoma cell-specific binding molecule, glycyrrhetinic acid (GA), to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by Fourier transformed infrared spectroscopy (FT-IR) and 1H-nuclear magnetic resonance (1H-NMR). By combining GA-CTS and 5-FU (5-fluorouracil), we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 217.2 nm, a drug loading of 1.56% and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained release system comprising three distinct phases of quick, steady and slow release. We demonstrated that the nanoparticle accumulated in the liver. In vitro data indicated that it had a dose- and time-dependent anti-cancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. Additionally, GA-CTS/5-FU significantly inhibited the growth of drug-resistant hepatoma, which may compensate for the drug-resistance of 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited tumor growth, resulting in increased survival time.
doi:10.3390/md11093517
PMCID: PMC3806472  PMID: 24048270
hepatic carcinoma; regulatory T-cells; glycyrrhetinic acid; targeted therapy; 5-fluorouracil
15.  Glycyrrhetinic acid-modified chitosan nanoparticles enhanced the effect of 5-fluorouracil in murine liver cancer model via regulatory T-cells 
Modified chitosan nanoparticles are a promising platform for drug, such as 5-fluorouracil (5-FU), gene, and vaccine delivery. Here, we used chitosan and hepatoma cell-specific binding molecule glycyrrhetinic acid (GA) to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance. By combining GA-CTS and 5-FU, we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 193.7 nm, drug loading of 1.56%, and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained-release system comprising three distinct phases of quick, steady, and slow release. In vitro data indicated that it had a dose- and time-dependent anticancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited cancer cell proliferation, resulting in increased survival time. The antitumor mechanisms for GA-CTS/5-FU nanoparticle were possibly associated with an increased expression of regulatory T-cells, decreased expression of cytotoxic T-cell and natural killer cells, and reduced levels of interleukin-2 and interferon gamma.
doi:10.2147/DDDT.S52809
PMCID: PMC3810199  PMID: 24187487
hepatic carcinoma; regulatory T cells; glycyrrhetinic acid; targeted therapy; 5-fluorouracil
16.  Propargylaminyl 3α-hy­droxy-11-oxo-18β-olean-12-en-29-oate 
The title compound, C33H49NO3, is the propargyl­amide of 18β-glycyrrhetinic acid, a penta­cyclic triterpenoid of inter­est as a therapeutic agent. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring C in a half-chair conformation. In the crystal, the terminal N-propargylcarboxamide group has remarkable structural effects on weak hydrogen-bond-like inter­actions. Particularly noteworthy are an inter­molecular O—H⋯π inter­action accepted side-on by the terminal alkyne group [O⋯C = 3.097 (2) and 3.356 (2) Å] and a short inter­molecular C—H⋯O inter­action [C⋯O = 3.115 (2) Å] donated by the alkyne C—H group. An N—H⋯O [N⋯O = 3.251 (2) Å] and a Calkyl—H⋯O [C⋯O = 3.254 (2) Å] interaction complement the crystal structure.
doi:10.1107/S1600536811043534
PMCID: PMC3247445  PMID: 22220063
17.  Optimized synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and their characteristics 
The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross-link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (Cmax) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model.
doi:10.2147/IJN.S55255
PMCID: PMC3908832  PMID: 24493926
liver cancer; targeted therapy; chemotherapy; pharmacokinetics efficacy
18.  Synthesis and Proteasome Inhibition of Glycyrrhetinic Acid Derivatives 
Bioorganic & medicinal chemistry  2008;16(14):6696-6701.
This study discovered that glycyrrhetinic acid inhibited the human 20S proteasome at 22.3 µM. Esterification of the C-3 hydroxyl group on glycyrrhetinic acid with various carboxylic acid reagents yielded a series of analogs with marked improved potency. Among the derivatives, glycyrrhetinic acid 3-O-isophthalate (17) was the most potent compound with IC50 of 0.22 µM, which was approximately 100-fold more potent than glycyrrhetinic acid.
doi:10.1016/j.bmc.2008.05.078
PMCID: PMC2579312  PMID: 18562200
Glycyrrhetinic acid; proteasome inhibitor; triterpene
19.  Incidence of hand eczema in female Swedish hairdressers 
Objective
To estimate the occurrence of hand eczema in hairdressers in Sweden.
Methods
The occurrence of hand eczema was estimated in a Swedish longitudinal retrospective cohort study including all female graduates from vocational schools for hairdressers from 1970 to 1995. A stratified sample from the general population acted as controls. A self‐administered questionnaire including questions on the occurrence of hand eczema, skin atopy, working periods and number of hair treatments performed per week was sent to the participants. Incidence rate ratios (IRRs) of hand eczema were estimated.
Results
The incidence rate of hand eczema in hairdressers was 23.8 cases/1000 person‐years, whereas in hairdressers who were aged <25 years it was 37.1/1000 person‐years. The corresponding IRR for hairdressers compared with controls was 2.5 (95% confidence interval (CI) 2.2 to 2.8), and that for younger hairdressers was 3.1 (95% CI 2.6 to 3.5). The mean age at onset of hand eczema was 21.6 years for hairdressers and 21.2 years for controls. The 1‐year prevalence of hand eczema was 18.0% for hairdressers and 12.1% for controls. A large number of hair treatments involving exposure to skin irritants and sensitisers were reported. The incidence rate of hand eczema was higher among individuals with a history of childhood eczema, both for hairdressers and for controls, giving an (age‐adjusted) IRR of 1.9 and 2.2, respectively. The attributable fraction of hand eczema from skin atopy was 9.6%. A synergistic effect of skin atopy and hairdressing was found on the occurrence of hand eczema. The relative excess risk due to interaction was 1.21 (95% CI 0.21 to 2.21; p = 0.01).
Conclusion
Hairdressers are highly exposed to skin‐damaging substances. The self‐reported incidence of hand eczema was substantially higher in female hairdressers than in controls from the general population and than that found previously in register‐based studies. For many individuals, onset of hand eczema occurs early in life. Only about 10% of the hand eczema cases among hairdressers would be prevented if no one with skin atopy entered the trade.
doi:10.1136/oem.2005.026211
PMCID: PMC2092538  PMID: 17053020
20.  Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial 
Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age.
Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial.
Setting Adelaide, South Australia.
Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial.
Interventions The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks’ gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA.
Main outcome measure Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age.
Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen.
Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood.
Trial registration Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).
doi:10.1136/bmj.e184
PMCID: PMC3269207  PMID: 22294737
21.  Glycyrrhetinic Acid-Poly(ethylene glycol)-glycyrrhetinic Acid Tri-Block Conjugates Based Self-Assembled Micelles for Hepatic Targeted Delivery of Poorly Water Soluble Drug 
The Scientific World Journal  2013;2013:913654.
The triblock 18β-glycyrrhetinic acid-poly(ethylene glycol)-18β-glycyrrhetinic acid conjugates (GA-PEG-GA) based self-assembled micelles were synthesized and characterized by FTIR, NMR, transmission electron microscopy, and particle size analysis. The GA-PEG-GA conjugates having the critical micelle concentration of 6 × 10−5 M were used to form nanosized micelles, with mean diameters of 159.21 ± 2.2 nm, and then paclitaxel (PTX) was incorporated into GA-PEG-GA micelles by self-assembly method. The physicochemical properties of the PTX loaded GA-PEG-GA micelles were evaluated including in vitro cellular uptake, cytotoxicity, drug release profile, and in vivo tissue distribution. The results demonstrate that the GA-PEG-GA micelles had low cytotoxicity and good ability of selectively delivering drug to hepatic cells in vitro and in vivo by the targeting moiety glycyrrhetinic acid. In conclusion, the GA-PEG-GA conjugates have potential medical applications for targeted delivery of poor soluble drug delivery.
doi:10.1155/2013/913654
PMCID: PMC3858885  PMID: 24376388
22.  Alitretinoin – its use in intractable hand eczema and other potential indications 
Chronic hand eczema is a significant cause of morbidity. A number of treatments are traditionally used, and often useful, but in spite of this a sizeable group of patients develop chronic recalcitrant hand eczema. Retinoids are known to influence keratinization and inflammation, and acitretin has shown some effect in the treatment of chronic hand eczema. Alitretinoin (9-cis-retinoic acid) is a panagonist retinoid binding to all six known retinoid receptors (RAR-α, -β, -γ and RXR-α, -β, -γ). Several studies have been carried out with this new drug, and it has been shown to be effective in 28% to 89% of patients with previously intractable hand eczema. In addition, alitretinoin appears to have some potential in the treatment of AIDS-related Kaposi sarcoma. Attempts to use the drug in secondary prophylaxis has shown some promise in former tobacco smokers, whereas no effect was seen in patients with cervical intraepithelial neoplasia. Currently, the primary therapeutic potential of alitretinoin appears to be the treatment of chronic recalcitrant hand eczema, which also forms a large and hitherto neglected group of patients.
PMCID: PMC2769244  PMID: 19920921
alitretinoin; hand; eczema; dermatitis
23.  Low breast milk levels of long-chain n-3 fatty acids in allergic women, despite frequent fish intake 
Clinical and Experimental Allergy  2011;41(4):505-515.
Background
Long-chain n-3 polyunsaturated fatty acids (PUFAs) have immune regulating and anti-inflammatory effects. However, their role in allergic disease is unclear. Allergic diseases are immunologically heterogeneous, and we hypothesized that n-3 fatty acid composition in serum and breast milk may vary according to clinical manifestations. Further, animal studies have shown reduction of serum-PUFA levels during allergic inflammation.
Objective
To investigate fatty acid composition in breast milk and serum from women with different atopic disease manifestations. Secondly, to determine whether low PUFA levels reflected insufficient intakes.
Methods
Fatty acids were analysed in breast milk and serum of women with atopic eczema and respiratory allergy (n=16), only respiratory allergy (n=7), as well as healthy women (n=22). Dietary intake of foods expected to affect long-chain n-3 PUFA levels were estimated by food-frequency questionnaire. The fatty acid pattern was related to diagnostic group and intake of relevant food items using a multivariate pattern recognition method (partial least squares projections to latent structures and discriminant analysis).
Results
Women with a combination of eczema and respiratory allergy had lower breast milk levels of several PUFAs (arachidonic acid, eicosapentaenoic acid, EPA, docosahexaenoic acid, DHA, and docosapentaenoic acid, DPA), and a lower ratio of long-chain n-3 PUFAs/n-6 PUFAs. Their PUFA levels differed not only from that of healthy women, but also from that of women with only respiratory allergy. The latter had a fatty acid pattern similar to that of healthy women. Despite low EPA, DHA and DPA levels women with eczema and respiratory allergy consumed no less fish than did healthy women.
Conclusion & Clinical Relevance
Our data suggest that reduced levels of long-chain n-3 fatty acids in serum and breast milk characterize women with extensive allergic disease including eczema, and are not related to low fish intake. Consumption of PUFAs during the allergic process may explain these findings.
doi:10.1111/j.1365-2222.2010.03678.x
PMCID: PMC3085074  PMID: 21338426
allergy; atopic eczema; atopy; breast milk; DHA; EPA; fatty acids
24.  Interplay of Filaggrin Loss-of-Function Variants, Allergic Sensitization, and Eczema in a Longitudinal Study Covering Infancy to 18 Years of Age 
PLoS ONE  2012;7(3):e32721.
Background
Immune specific genes as well as genes regulating the formation of skin barrier are major determinants for eczema manifestation. There is a debate as to whether allergic sensitization and filaggrin gene (FLG) variants lead to eczema or FLG variants and eczema increase the risk of allergic sensitization. To investigate the time-order between eczema and allergic sensitization with respect to FLG variants, data from a large prospective study covering infancy to late adolescence were analyzed.
Methodology/Principal Findings
Repeated measurements of eczema and allergic sensitization (documented by skin prick tests) at ages 1, 2, 4, 10, and 18 years were ascertained in the Isle of Wight birth cohort (n = 1,456). Three transition periods were analyzed: age 1-or-2 to 4, 4 to 10, and 10 to 18 years. FLG variants were genotyped in 1,150 participants. Over the three transition periods, in temporal sequence analyses of initially eczema-free participants, the combined effect of FLG variants and allergic sensitization showed a 2.92-fold (95% CI: 1.47–5.77) increased risk ratio (RR) of eczema in subsequent examinations. This overall risk was more pronounced at a younger age (transition period 1-or-2 to 4, RR = 6.47, 95% CI: 1.96–21.33). In contrast, FLG variants in combination with eczema showed a weaker, but significant, risk ratio for subsequent allergic sensitization only up to 10 years of age.
Conclusions/Significance
Taking the time order into account, this prospective study demonstrates for the first time, that a combination of FLG variants and allergic sensitization increased the risk of eczema in subsequent years. Also FLG variants interacted with eczema and increased the risk of subsequent allergic sensitization, which, was limited to the younger age. Hence, early restoration of defective skin barrier could prevent allergic sensitization and subsequently reduce the risk of eczema development.
doi:10.1371/journal.pone.0032721
PMCID: PMC3293849  PMID: 22403702
25.  Unifying Mechanisms of Action of the Anticancer Activities of Triterpenoids and Synthetic Analogs 
Triterpenoids such as betulinic acid (BA) and synthetic analogs of oleanolic acid [2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)] and glycyrrhetinic acid [2-cyano-3,11-dioxo-18β-oleana-1,12-dien-30-oc acid (CDODA)] are potent anticancer agents that exhibit antiproliferative, antiangiogenic, anti-inflammatory and pro-apoptotic activities. Although their effects on multiple pathways have been reported, unifying mechanisms of action have not been reported. Studies in this laboratory have now demonstrated that several triterpenoids including BA and some derivatives, celastrol, methyl ursolatee, β-boswellic acid derivatives, and the synthetic analogs CDDO, CDODA and their esters decreased expression of specificity protein (Sp) transcription factors and several pro-oncogenic Sp-regulated genes in multiple cancer cell lines. The mechanisms of this response are both compound- and cell context-dependent and include activation of both proteasome-dependent and -independent pathways. Triterpenoid-mediated induction of reactive oxygen species (ROS) has now been characterized as an important proteasome-independent pathway for downregulation of Sp transcription factors. ROS decreases expression of microRNA-27a (miR-27a) and miR-20a/miR-17-5p and this results in the induction of the transcriptional “Sp-repressors” ZBTB10 and ZBTB4, respectively, which in turn downregulate Sp and Sp-regulated genes. Triterpenoids also activate or deactive nuclear receptors and G-protein coupled receptors, and these pathways contribute to their antitumorigenic activity and may also play a role in targeting Sp1, Sp3 and Sp4 which are highly overexpressed in multiple cancers and appear to be important for maintaining the cancer phenotype.
PMCID: PMC3532564  PMID: 22583404
Sp transcription factors; downregulation; reactive oxygen species

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