János Garai

Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: Phytoestrogens and xenoestrogens

Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens. Since the discovery of the estrus-inducing effects of some plant products in 1926, considerable effort has been devoted to the isolation and structural and pharmacological characterization of phytoestrogens. Recently, agricultural and industrial pollution has added anthropogenic estrogenic compounds to the list of environmental estrogens. Unlike phytoestrogens, these xenoestrogens tend to accumulate and persist in adipose tissue for decades and may cause long-lasting, adverse endocrine effects. Here we review the endocrine effects of known phytoestrogens and xenoestrogens with special emphasis on molecular structure-activity relationships. Phytoestrogens include flavonoids, isoflavonoids, chalcons, coumestans, stilbenes, lignans, ginsenosides and other saponins, as well as the recently discovered tetrahydrofurandiols. Fungal estrogenic compounds may enter the food chain via infested crops. Since some phytoestrogens have been shown to display organ-specific actions, pharmaceutical estrogen analogues with similar properties (selective estrogen receptor modulators, SERMs) are also discussed. Xenoestrogens include dichlorodiphenyltrichloroethane (DDT) and its metabolites, bisphenols, alkylphenols, dichlorophenols, methoxychlor, chlordecone, polychlorinated benzol derivatives (PCBs), and dioxins. While most of these compounds act through estrogen receptors alpha and beta, some of their effects may be mediated by other nuclear or membrane-bound receptors or receptor-independent mechanisms. Some might also interfere with the production and metabolism of ovarian estrogens. Better understanding of the molecular pharmacology of phyto- and xenoestrogens may result in the development of novel compounds with therapeutic utility and improved environmental protection.

Endometriosis: Harmful survival of an ectopic tissue

Endometriosis results from implantation of endometrial tissue outside the uterine cavity. Endometriosis might remain asymptomatic and discovered accidentally. However, it may cause symptoms, which include chronic pelvic pain, bleeding, infertility, and increases susceptibility to development of adenocarcinoma. The most prevailing hypothesis is that endometriosis results from implantation of endometrial tissue that gains access to peritoneal cavity by retrograde flow during menstruation. The factors contributing to the establishment and persistence of the endometriotic lesions (plaques) most probably include abnormalities of the genital tract, genetic predisposition, hormonal imbalance, altered immune surveillance, inflammatory response and abnormal regulation of the endometrial cells. The mediators that contribute to survival and progression of endometriosis are likely involved in the development of the symptoms of this process. Genomic studies have started to delineate the wide array of mediators involved and the complex genetic background required in the development of endometriosis. This review summarizes our current knowledge regarding the pathogenesis of endometriosis, including progress made with transgenic animals, and a clinical perspective on the diagnosis and management of this common process.

Macrophage migration inhibitory factor (MIF) tautomerase inhibitors as potential novel anti-inflammatory agents: current developments.

Macrophage migration inhibitory factor (MIF), the pro-inflammatory cytokine, first described in 1966, plays an essential role in both, innate and adaptive immune response. It has been implicated in tumour growth and angiogenesis and it exerts an antagonistic action against glucocorticoid immunosuppressive effect. Its perplexing enzymatic tautomerase activity has attracted considerable interest in the last decade. It has been suggested, that a multitude of autoimmune/inflammatory/neoplastic disease states might benefit from therapeutic measures, targeting MIF. Hence, small molecule inhibitors of MIF are relentlessly sought as potential anti-inflammatory (antitumour) agents, while a true in vivo substrate for MIF still remains unidentified. One of the first studied MIF inhibitor group was the D-dopachrome family, and its carboxyderivatives have shown good inhibitory effect, as well as the fluorosubstituted phenylpyruvic acid class. The substance ISO-1 of isoxazoline skeleton was the first small molecular inhibitor of MIF, not related to its known substrates. N-acetyl-p-benzoquinone, an acetaminophen metabolite and its synthetic derivatives exerted submicromolar IC(50) values. An acetylenic compound, the 2-oxo-4-phenyl-3-butynoate is a potent active-site-directed irreversible inhibitor of the phenyl pyruvate tautomerase activity of MIF. Some oxygen heterocycles, coumarines and chromenes, have also drawn attention as MIF inhibitors. The alpha,beta-unsaturated carbonyl compounds constitute a large novel class of MIF inhibitors. Several potent inhibitors were found among the cinnamic acid derivatives, thealpha,beta-unsaturated cyclic ketones, and the natural curcuminoids. Some other plant derived compounds were also studied. One of the latest developments in the field is the synthesis of AVP-13546, an exceptionally potent inhibitor. The structural pattern of MIF enzyme inhibitors exhibits wide variety; compounds having quite different molecular backbones belong to the MIF inhibitor family. In this paper, the separate classes of MIF inhibitors are discussed.

Influence of dextran-70 on systemic inflammatory response and myocardial ischaemia-reperfusion following cardiac operations

IntroductionExperimental studies have demonstrated that dextran-70 reduces the leukocyte–endothelium interaction, but clinical evidence is still lacking. Our objective was to justify the anti-inflammatory effect of dextran-70 following cardiac operations.MethodsForty patients undergoing coronary bypass surgery (n = 32) or aortic valve replacement (n = 8) were enrolled in this prospective, randomized, double-blind study. Two groups were formed. In group A (n = 20), dextran-70 infusion was administered at a dose of 7.5 ml/kg before the initiation of cardiopulmonary bypass and at a dose of 12.5 ml/kg after the cessation of cardiopulmonary bypass. Group B served as a control with identical amounts of gelatin infusion (n = 20). The plasma concentration of procalcitonin, C-reactive protein, IL 6, IL 6r, IL 8, IL 10, soluble endothelial leukocyte adhesion molecule-1, soluble intercellular adhesion molecule-1, cardiac troponin-I and various haemodynamic parameters were measured in the perioperative period. Multivariate methods were used for statistical analysis.ResultsIn group A, lower peak (median) plasma levels of procalcitonin (0.2 versus 1.4, p < 0.001), IL 8 (5.6 versus 94.8, p < 0.001), IL 10 (47.2 versus 209.7, p = 0.001), endothelial leukocyte adhesion molecule-1 (88.5 versus 130.6, p = 0.033), intercellular adhesion molecule-1 (806.7 versus 1,375.7, P = 0.001) and troponin-I (0.22 versus 0.66, p = 0.018) were found. There was no significant difference in IL 6, IL-6r and C-reactive protein values between groups. Higher figures of the cardiac index (p = 0.010) along with reduced systemic vascular resistance (p = 0.005) were noted in group A.ConclusionOur investigation demonstrated that the use of dextran-70 reduces the systemic inflammatory response and cardiac troponin-I release following cardiac operation.Trial registration numberISRCTN38289094.

Thrombosis Preventive Potential of Chicory Coffee Consumption: A Clinical Study

The protective effects of plant polyphenol intake on cardiovascular morbidity and mortality are widely acknowledged. Caffeine‐free chicory coffee is a rich source of plant phenolics, including caffeic acid, which inhibits in vitro platelet aggregation, and also phenylpyruvate tautomerase enzymatic activity of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF). To assess whether chicory coffee consumption might confer cardiovascular benefits a clinical intervention study was performed with 27 healthy volunteers, who consumed 300 mL chicory coffee every day for 1 week. The dietary intervention produced variable effects on platelet aggregation, depending on the inducer used for the aggregation test. Whole blood and plasma viscosity were both significantly decreased, along with serum MIF levels, after 1 week of chicory coffee consumption. Moreover, significant improvements were seen in red blood cell deformability. No changes in hematocrit, fibrinogen level or red blood cell counts were detected. The full spectrum of these effects is unlikely to be attributable to a single compound present in chicory coffee, nevertheless, the phenolics, including caffeic acid, are expected to play a substantial role. In conclusion, our study offers an encouraging starting‐point to delineate the antithrombotic and antiinflammatory effects of phenolic compounds found in chicory coffee. Copyright

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium.

Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly in sensory nerves are activated by inflammatory stimuli and mediate inflammation and pain. Although they have been shown in the human endometrium, their regulation and function are unknown. Therefore, we investigated their estrogen- and progesterone-dependent alterations in the rat endometrium in comparison with the estrogen-regulated inflammatory cytokine macrophage migration inhibitory factor (MIF). Four-week-old (sexually immature) and four-month-old (sexually mature) female rats were treated with the non-selective estrogen receptor (ER) agonist diethylstilboestrol (DES), progesterone and their combination, or ovariectomized. RT-PCR and immunohistochemistry were performed to determine mRNA and protein expression levels respectively. Channel function was investigated with ratiometric [Ca(2+)]i measurement in cultured primary rat endometrial cells. Both TRP receptors and MIF were detected in the endometrium at mRNA and protein levels, and their localizations were similar. Immunostaining was observed in the immature epithelium, while stromal, glandular and epithelial positivity were observed in adults. Functionally active TRP receptor proteins were shown in endometrial cells by activation-induced calcium influx. In adults, Trpa1 and Trpv1 mRNA levels were significantly up-regulated after DES treatment. TRPA1 increased after every treatment, but TRPV1 remained unchanged following the combined treatment and ovariectomy. In immature rats, DES treatment resulted in increased mRNA expression of both channels and elevated TRPV1 immunopositivity. MIF expression changed in parallel with TRPA1/TRPV1 in most cases. DES up-regulated Trpa1, Trpv1 and Mif mRNA levels in endometrial cell cultures, but 17β-oestradiol having ERα-selective potency increased only the expression of Trpv1. We provide the first evidence for TRPA1/TRPV1 expression and their estrogen-induced up-regulation in the rat endometrium in correlation with the MIF.

Pelvic pain in endometriosis: Painkillers or sport to alleviate symptoms?

To assess potential individual factors influencing quality of life and pain scores of patients suffering from histologically confirmed endometriosis. Study using a questionnaire among patients of reproductive age undergoing laparoscopy with a presumed diagnosis of endometriosis. Details of fertility, previous treatments and quality of life, sexual activity, as well as linear pain scores for several symptoms, were recorded. Details of intraoperative findings were also collected and only those data were used where endometriosis was intraoperatively and histologically proven. A questionnaire before surgery gathered information from women on the following groups of variables: age, marital status, education, reproductive and medical history including previous pregnancies and parity, knowledge of accompanying pelvic disorders, regular sport activity, as well as general quality of life estimates including self-image. Pelvic pain was scored using a visual analogue scale. Data were statistically evaluated. Eighty-one patients complaining about persistent pelvic pain were later intraoperatively and histologically proven to have endometriosis. Thirty-one of them (38.2%) reported regular sport as part of their daily life schedule while 50 of them (61.8%) performed no physical activity at all. Fourteen patients among regular exercisers and 33 patients among those without physical activity reported the effectiveness of painkillers for pelvic pain, corresponding to 45.1% and 66% of these subgroups, respectively (difference statistically significant, p<0.05). Based on our results, we can conclude, that taking painkillers might be less effective among endometriosis patients performing regular daily sport activities, and, thus it might impose them to an unnecessary burden of possible side-effects.

Estrogen-inducible uterine flavonoid binding sites: is it time to reconsider?

Epidemiological data support the beneficial effect of plant flavonoids on human health including anti-inflammatory and cancer preventing actions. The phytoestrogen flavonoids might interfere with estrogen action. The possible relations between the steroid- and the flavonoid-signalling in animal and plant cells have been addressed in numerous studies in the past decade. In search for possible sites of conjunction between these phenomena the post-receptor targets must not be disregarded. The estrogen-inducible type II estrogen binding sites of rat uteri have first been reported 25 years ago by Clark and coworkers [Biochem. Biophys. Res. Commun. 81 (1978) 1]. These sites are known to bind catecholic flavonoids with considerable affinity. Behaviour of the tyrosinase-like enzymatic activity associated with these sites appeared reminiscent to the recently described dopachrome oxidase or tautomerase activity exhibited by the cytokine macrophage migration inhibitory factor (MIF) inasmuch as it also accepts a broad range of catecholic melanogenic precursors. Therefore we assessed, whether the known type II ligand flavonoids interfere with the MIF tautomerase. We report here, that luteolin and quercetin have a biphasic effect on the enol-keto conversion of phenylpyruvate mediated by MIF tautomerase. We also demonstrate the presence of MIF immunoreactivity by Western blotting in rat uterine nuclear extracts prepared according to the method that yields high type II binding activity. These data support the possible participation of MIF in type II estrogen binding phenomena.

Longitudinal changes in macrophage migration inhibitory factor in breast milk during the first three months of lactation.

The presence of macrophage migration inhibitory factor (MIF) in breast milk has been reported before, but its concentration at distinct phases of lactation has not yet been delineated. We have measured the MIF content in the aqueous phase of 63 milk samples from 21 mothers at postpartum days 5, 12 and 84 by enzyme-linked immunosorbent assay. MIF declined consistently from 44.5±40.3 ng/ml at day 5 to 20.3±12.9 ng/ml at day 84, but no similar trend was found in the ng/mg protein values. MIF may play a relevant role in the complex immunological interface between the mother and her infant.

A rectus diastasis prevalenciája, lehetséges rizikófaktorai és szövődményei

INTRODUCTION: There is scant knowledge on diastasis recti which occurs mostly in 3rd trimester of pregnancy. AIM: Our aim was to assign the prevalence of diastasis recti and the possible risk factors and to investigate its association with some chronical diseases, like low back pain and urinary incontinence. METHOD: 200 womens interrectus distance was measured who filled out a self-made diastasis recti questionnaire, the SF-36, Oswestry Disability Index and the International Consultation on Incontinence Modular Questionnaire - Urinary Incontinence Short Form questionnaires. RESULTS: Prevalence of the condition was 46.5%. In case of risk factors, relationship between number of deliveries and interrectus distance was significant. We found a significant difference in quality of life, in presence of low back pain and urinary incontinence between the normal and the abnormal group. CONCLUSIONS: In line with the literature we found, that diastasis recti can predispose on serious sequelae, hence on decreased quality of life. Orv. Hetil., 2017, 158(12), 454-460.INTRODUCTION There is scant knowledge on diastasis recti which occurs mostly in 3rd trimester of pregnancy. AIM Our aim was to assign the prevalence of diastasis recti and the possible risk factors and to investigate its association with some chronical diseases, like low back pain and urinary incontinence. METHOD 200 womens interrectus distance was measured who filled out a self-made diastasis recti questionnaire, the SF-36, Oswestry Disability Index and the International Consultation on Incontinence Modular Questionnaire - Urinary Incontinence Short Form questionnaires. RESULTS Prevalence of the condition was 46.5%. In case of risk factors, relationship between number of deliveries and interrectus distance was significant. We found a significant difference in quality of life, in presence of low back pain and urinary incontinence between the normal and the abnormal group. CONCLUSIONS In line with the literature we found, that diastasis recti can predispose on serious sequelae, hence on decreased quality of life. Orv. Hetil., 2017, 158(12), 454-460.