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Co-individuazione delle isoforme di mRNA per il recettore dei mineralcorticoidi (MR) e dell' enzima 11ß-idrossisteroide deidrogenasi in cellule e tessuti umani atipici, rispondenti all'aldosterone. Studio particolareggiato in pazienti affetti da iperaldosteronismo primitivo e ricerca di mutazioni nel gene MR in una famiglia con diagnosi di pseudo-ipoaldosteronismo.
Full text linkThe steroid hormone aldosterone, that normally controls the urinary Na+/K+ balance, and the osmolarity in the kidney, colon, salivary and swab glands epithelial tissues, exerts also many different effects, by binding to the mineralocorticoid receptor (MR). This receptor binds both aldosterone and glucocorticoids (mostly cortisol) with approximately the same affinity. However, cortisol has a 1000-fold higher concentration in plasma than that of aldosterone. In its classical target tissues, the mineralocorticoid selectivity mainly depends on the enzymatic activity of the type 2 11ß-hydroxysteroid dehydrogenase (11ß -HSD2), which converts cortisol into inactive cortisone, a corticosteroid that doesn't bind to the MR. The human MR gene (hMR) maps on chromosome 4 and contains 8 coding exons, with the start of the open reading frame (ORF) in the exon 2, which gives a 984 aminoacid product. The untranslated exon 1, which exists in the two isoforms 1? and 1ß, may give rise, by alternative splicing, to the hMR? and hMRß mRNA variants. The hMRß seems to be expressed only in some tissues and cell types.
In 2001, two other hMR mRNA variants were described and they were called hMR?5 and hMR?5,6, because they lack the exon 5 or both exons 5 and 6, respectively. The hMR? transcript isoforms, first detected in the kidney, encode for a receptor which lack a fragment or the whole LBD domain, and they are both widely expressed among tissues, where they act as transcription factors that do not depend upon the ligand aldosterone.
In this work, I first demonstrated, by RT-PCR assays, the expression of hMR gene in spermatozoa, even though, in these cells, it was less detectable than in human mononuclear leukocytes (LMN). These important data were confirmed by immunofluorescence, in which the hMR protein was detectable in the middle piece and in the tail of the spermatozoa. These results may provide useful insight into mechanisms that can modify sperm motility in the presence of aldosterone in the milieu.
It is well known, from the scientific literature, that the activation of a number of genes, consequently to the specific MR-aldosterone interaction, may lead to the synthesis of some pro-inflammatory substances, in the heart, kidney, and in the vascular endothelium. In primary hyperaldosteronism, the presence of high aldosterone plasma levels may finally cause fibrosis in the same districts. The first steps of the inflammatory processes are characterized by a massive invasion of LMN, so, in the present research, I analyzed, by RT-PCR reactions, the expression of hMR gene variants in LMN from patients with Conn syndrome, and in both the normal adrenal cortex tissue, and in the adjacent adenoma producing aldosterone (APA) samples. I demonstrated a variable expression of the hMRß isoform, in comparison with the hMR? variant, which is homogeneously detectable in all the analyzed samples, and it was found that the hMRß mRNA was less expressed in the APA tissues, than in the normal adrenal tissue and in the LMN of the same patients.
In the same samples, I also verified the co-expression of mRNA for both the type 1 and 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD 1 and 2). A very interesting outcome from this step of my study was the demonstration of the 11ß -HSD type 2 expression in LMN of most of the patients with primary aldosteronism, while the same mRNA was not detectable in LMN from healthy volunteers. These important results, if they are confirmed in a significantly greater number of patients, would provide more information in order to predict the presence of a primary aldosteronism itself.
In this work, I also analyzed, by RT-PCR, the expression of the above mentioned genes in five normal tissue samples from human larynx. Even in this case, the hMR?, hMRß and the 11ß-HSD type 2 mRNAs were all detectable in the larynx tissue, and so this can be considered as a novel tissue specifically responsive, in a genomic manner, to aldosterone by its interaction with MR. The meaning of this result will be investigate in the future.
Many human diseases depend upon a number of important mutations in almost all the hMR exons, causing type I pseudo-hypoaldosteronism (PHA I), which mimics the absence of aldosterone, even if it is synthesized in a great amount. In the last period of my work, I investigated the hMR gene for mutations in each exon, in a family with PHA I, composed by a newborn, that was identified as the case-control, and their parents. Since no important nucleotide substitutions was revealed in the analyzed coding regions, this family is probably affected by the renal variant of the above mentioned diseases, where the mutations involve the gene encoding for the epithelial sodium channels subunits in the kidney
Spontaneous resolution of idiopathic aldosteronism after long-term treatment with potassium canrenoate.
No full textThe results of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study4 and the Randomized Aldactone Evaluation Study5 in fact show that aldosterone receptor blockers are effective in preventing cardiovascular complications, independent from the aldosterone value. Our data can strengthen this concept, showing that aldosterone receptor blockers also have a beneficial effect at the level of glomerulosa, restoring a normal reactivity to angiotensin II.
In conclusion, our data are consistent either with an exhaustion of the biochemical picture of PA in patients treated for the long term with KC, with reversal of PA to essential hypertension, or with an age-related reduction of renin and aldosterone with restoration of normal reactivity of glomerulosa to aldosterone
In vitro effects of glycyrrhetinic acid on the growth of clinical isolates of Candida albicans.
No full textCompounds derived from Glycyrrhiza glabra L. root have been used widely for centuries for their numerous therapeutic properties. The present study aimed to test the in vitro activity against Candida albicans strains of the compound 18-beta glycyrrhetinic acid (18-beta GA), derived from the root of Glycyrrhiza species. This antimicrobial activity was assessed using the National Committee for Clinical Laboratory Standards (NCCLS) method on C. albicans strains that were isolated from patients with recurrent vulvovaginal candidiasis (RVVC). The in vitro growth of the C. albicans strains was markedly reduced, in a pH-dependent manner, by relatively low doses (6.2 microg/mL) of 18-beta GA. The results demonstrate that 18-beta GA is a promising biological alternative for the topical treatment of recurrent vulvovaginal candidiasis (RVVC)
A hypothesis on the death of the Greek philosopher Heraclitus
No full textSearching data in historical sources, we hypothesize that Heraclitus consumed an excess of licorice to reduce both thirst and hunger, due to the limited availability of other food outside Ephesus where Heraclitus lived. The prolonged intake of licoice could have led to sodium and water retention and probably to severe hypertension and dropsy, which in turn caused the death of the philosopher
Polycystic ovary syndrome: implications of corticotropin in the regulation of blood pressure, aldosterone, and androgen secretion.
No full textn a recent issue of Hypertension, Chen et al1 have described a correlation between androgen levels and blood pressure in young women with polycystic ovary syndrome (PCOS), and this correlation was independent from age, insulin resistance, obesity, and dyslipidemia. We would like to discuss other factors involved in the interpretation of these data.
High adrenal androgen levels in women with PCOS can also be related to an increase of corticotropin (ACTH). The major question is why ACTH could be responsible for an increase of adrenal androgens in PCOS. Previous reports have documented that patients with PCOS have reduced activity of 11β-hydroxysteroid dehydrogenase type 1, the enzyme that activates cortisone to cortisol.2 11β-Hydroxysteroid dehydrogenase type 1 may enhance the metabolic clearance rate of cortisol, thereby reducing negative feedback and increasing ACTH-dependent adrenal androgen production. It is interesting, at this point, that an extremely high increase of cortisone metabolites and of androgen concentrations are reported in some patients with PCOS and cortisone reductase deficiency.3
In a recent paper by Cascella et al,4 a positive correlation was found between aldosterone and mean blood pressure in patients with PCOS and, more interestingly, between aldosterone and C- reactive protein, metabolic patterns, and intima-media thickness. Both androgens1 and aldosterone4 correlate with blood pressure, and these findings are consistent with chronic ACTH drive in adrenals of patients with PCOS.
In fact, whereas administration of high amounts of ACTH for several days or 11-hydroxylase deficiency is associated with suppression of aldosterone and increase of deoxycorticosterone, a chronic ACTH drive because of a partial defect of 11β-hydroxysteroid dehydrogenase type 1 could activate aldosterone synthase at the level of adrenal glomerulosa and androgen secretion by the adrenal reticularis. We, therefore, suggest that a relative chronic increase of ACTH related to a slight deficiency of 11β-hydroxysteroid dehydrogenase type 1 can explain the reported hormonal pattern of these subjects.
The correlation among aldosterone, oxidative stress, metabolism abnormalities, and blood pressure is consistent with a primary involvement of aldosterone and not of androgens in the increase of blood pressure. These data also support the possibility of therapy with spironolactone in patients with PCOS. The drug blocks both the proinflammatory status because of aldosterone binding to mineralocorticoid receptors and the clinical picture of hyperandrogenism because of the binding of androgens to androgen receptors. We have recently stressed these concepts in a study of women with PCOS.
Antiviral effects of Glycyrrhiza species
Full text linkHistorical sources for the use of Glycyrrhiza species include ancient manuscripts from China, India and Greece. They all mention its use for symptoms of viral respiratory tract infections and hepatitis. Randomized controlled trials confirmed that the Glycyrrhiza glabra derived compound glycyrrhizin and its derivatives reduced hepatocellular damage in chronic hepatitis B and C. In hepatitis C virus-induced cirrhosis the risk of hepatocellular carcinoma was reduced. Animal studies demonstrated a reduction of mortality and viral activity in herpes simplex virus encephalitis and influenza A virus pneumonia. In vitro studies revealed antiviral activity against HIV-1, SARS related coronavirus, respiratory syncytial virus, arboviruses, vaccinia virus and vesicular stomatitis virus. Mechanisms for antiviral activity of Glycyrrhiza spp. include reduced transport to the membrane and sialylation of hepatitis B virus surface antigen, reduction of membrane fluidity leading to inhibition of fusion of the viral membrane of HIV-1 with the cell, induction of interferon gamma in T-cells, inhibition of phosphorylating enzymes in vesicular stomatitis virus infection and reduction of viral latency. Future research needs to explore the potency of compounds derived from licorice in prevention and treatment of influenza A virus pneumonia and as an adjuvant treatment in patients infected with HIV resistant to antiretroviral drugs
Treatment of polycystic ovary syndrome with spironolactone plus licorice.
No full textOBJECTIVE:The aim of the study was to compare the effect of spironolactone (antagonist of mineralocorticoid and androgen receptors) versus spironolactone plus licorice (agonist of mineralocorticoid receptors and mild inhibitor of androgen synthesis) on plasma renin activity, aldosterone and androgen levels in women with polycystic ovary syndrome (PCOS).
STUDY DESIGN:Thirty-two women with PCOS were divided into two groups: 16 received 100 mg spironolactone and 16 spironolactone plus 3.5 g of licorice a day. Blood pressure, body mass index, serum electrolytes, plasma renin activity, plasma aldosterone and cortisol, serum testosterone, and urinary tetrahydrocortisol/tetrahydrocortisone ratio were measured before and during treatment.
RESULTS:Mean blood pressure was significantly reduced during spironolactone treatment, while it was unchanged in women receiving spironolactone plus licorice. Twenty percent of women treated with spironolactone and none treated with the addition of licorice complained of symptoms related to volume depletion. Consistently, the activation of the renin-aldosterone system was significantly lower during spironolactone plus licorice than with spironolactone alone. The prevalence of metrorrhagia was lower in the combined therapy.
CONCLUSIONS:In patients with PCOS the mineralocorticoid properties of licorice can reduce the prevalence of side effects related to the diuretic activity of spironolactone
Difficulties in the mutation analysis of plasminogen gene: a study in two patients with ligneous conjunctivitis.
No full textThe absence or very low levels of plasminogen cause a rare disabling disease called ligneous conjunctivitis, characterized by the growth of fibrin-rich pseudomembranes in the conjunctiva and on other mucosal surfaces. Several mutations have been detected in the plasminogen gene of patients affected with ligneous conjunctivitis. The human plasminogen gene, located on chromosome 6, has a marked homology with the genes belonging to the plasminogen-apo(a) family, and with a number of pseudogenes and plasminogen-like genes located on chromosome 2. This work describes a series of nucleotide variations related to genes other than the plasminogen one, found during the genetic characterization of plasminogen defect in two unrelated patients with ligneous conjunctivitis. The results of automated sequences of each exon and intron-exon boundaries were compared with those of the human plasminogen gene from the NCBI gene bank. In particular, a co-amplified gene on chromosome 2 mimicking a 14 bp deletion in exon 5 of the plasminogen gene was identified by sequencing two different bands obtained from a long run of the PCR exon 5 product in NuSieve agarose gel, and by PstI restriction enzyme analysis of the same amplicons. Moreover, 21 single nucleotide exchanges due to plasminogen-like genes co-amplification were observed, namely one in exon 1, two in exon 4, three in exons 3, 5 and 16, four in exon 13, and five in exon 17. In conclusion, these data confirm the difficulty of plasminogen genetic analysis and may help researchers to better identify the true plasminogen gene mutations causing molecular defects
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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