An association of boswellia, betaine and myo-inositol (Eumastós) in the treatment of mammographic breast density. A randomized, double-blind study

Mammographic breast density is a recognized risk factor for breast cancer. The causes that lead to the proliferation of the glandular breast tissue and, therefore, to an increase of breast density are still unclear. However, a treatment strategy to reduce the mammary density may bring about very relevant clinical outcomes in breast cancer prevention. Myo-inositol is a six-fold alcohol of cyclohexane, has already been proved to modulate different pathways: inflammatory, metabolic, oxidative and endocrine processes, in a wide array of human diseases, including cancer and the genesis of mammary gland and breast diseases, like fibrosis, as well as metabolic and endocrine cues. Similarly, boswellic acid and betaine (three-methyl glycine) both inhibit inflammation and exert protective effects on breast physiology. Based on this scientific background, we hypothesized that a combination including, boswellic acid, betaine and myo-inositol would be able to reduce breast density working on different pathways.OBJECTIVE: Mammographic breast density is a recognized risk factor for breast cancer. The causes that lead to the proliferation of the glandular breast tissue and, therefore, to an increase of breast density are still unclear. However, a treatment strategy to reduce the mammary density may bring about very relevant clinical outcomes in breast cancer prevention. Myo-inositol is a six-fold alcohol of cyclohexane, has already been proved to modulate different pathways: inflammatory, metabolic, oxidative and endocrine processes, in a wide array of human diseases, including cancer and the genesis of mammary gland and breast diseases, like fibrosis, as well as metabolic and endocrine cues. Similarly, boswellic acid and betaine (threemethyl glycine) both inhibit inflammation and exert protective effects on breast physiology. Based on this scientific background, we hypothesized that a combinat ion including, boswellic acid, betaine and myo-inositol would be able to reduce breast density working on different pathways. PATIENTS AND METHODS: In this study, seventy-six premenopausal women were randomly assigned to the placebo and the experimental drug arms (Eumastós®) for six months. RESULTS: After 6 months of treatment, statistically significant difference between the two groups was recorded on the breast density reduction (60% vs. 9%), using mammographic as well as ultrasound examination. CONCLUSIONS: Preliminary data collected here with support the starting assumptions,that the association comprising boswellic acid, betaine and myo-inositol significantly reduces mammary density, providing the first evidence for a new and safe approach for the management of mammographic density treatment

Schmidtea mediterranea phylogeography: an old species surviving on a few Mediterranean islands?

Schmidtea mediterranea (Platyhelminthes, Tricladida, Continenticola) is found in scattered localities on a few islands and in coastal areas of the western Mediterranean. Although S. mediterranea is the object of many regeneration studies, little is known about its evolutionary history. Its present distribution has been proposed to stem from the fragmentation and migration of the Corsica-Sardinia microplate during the formation of the western Mediterranean basin, which implies an ancient origin for the species. To test this hypothesis, we obtained a large number of samples from across its distribution area. Using known and new molecular markers and, for the first time in planarians, a molecular clock, we analysed the genetic variability and demographic parameters within the species and between its sexual and asexual populations to estimate when they diverged. Results: A total of 2 kb from three markers (COI, CYB and a nuclear intron N13) was amplified from ~200 specimens. Molecular data clustered the studied populations into three groups that correspond to the west, central and southeastern geographical locations of the current distribution of S. mediterranea. Mitochondrial genes show low haplotype and nucleotide diversity within populations but demonstrate higher values when all individuals are considered. The nuclear marker shows higher values of genetic diversity than the mitochondrial genes at the population level, but asexual populations present lower variability than the sexual ones. Neutrality tests are significant for some populations. Phylogenetic and dating analyses show the three groups to be monophyletic, with the west group being the basal group. The time when the diversification of the species occurred is between ~20 and ~4 mya, although the asexual nature of the western populations could have affected the dating analyses. Conclusions: S. mediterranea is an old species that is sparsely distributed in a harsh habitat, which is probably the consequence of the migration of the Corsica-Sardinia block. This species probably adapted to temperate climates in the middle of a changing Mediterranean climate that eventually became dry and hot. These data also suggest that in the mainland localities of Europe and Africa, sexual individuals of S. mediterranea are being replaced by asexual individuals that are either conspecific or are from other species that are better adapted to the Mediterranean climate

<i>Schmidtea mediterranea</i> phylogeography: an old species surviving on a few Mediterranean islands?

Background: Schmidtea mediterranea (Platyhelminthes, Tricladida, Continenticola) is found in scattered localities on a few islands and in coastal areas of the western Mediterranean. Although S. mediterranea is the object of many regeneration studies, little is known about its evolutionary history. Its present distribution has been proposed to stem from the fragmentation and migration of the Corsica-Sardinia microplate during the formation of the western Mediterranean basin, which implies an ancient origin for the species. To test this hypothesis, we obtained a large number of samples from across its distribution area. Using known and new molecular markers and, for the first time in planarians, a molecular clock, we analysed the genetic variability and demographic parameters within the species and between its sexual and asexual populations to estimate when they diverged. Results: A total of 2 kb from three markers (COI, CYB and a nuclear intron N13) was amplified from ~200 specimens. Molecular data clustered the studied populations into three groups that correspond to the west, central and southeastern geographical locations of the current distribution of S. mediterranea. Mitochondrial genes show low haplotype and nucleotide diversity within populations but demonstrate higher values when all individuals are considered. The nuclear marker shows higher values of genetic diversity than the mitochondrial genes at the population level, but asexual populations present lower variability than the sexual ones. Neutrality tests are significant for some populations. Phylogenetic and dating analyses show the three groups to be monophyletic, with the west group being the basal group. The time when the diversification of the species occurred is between ~20 and ~4 mya, although the asexual nature of the western populations could have affected the dating analyses. Conclusions: S. mediterranea is an old species that is sparsely distributed in a harsh habitat, which is probably the consequence of the migration of the Corsica-Sardinia block. This species probably adapted to temperate climates in the middle of a changing Mediterranean climate that eventually became dry and hot. These data also suggest that in the mainland localities of Europe and Africa, sexual individuals of S. mediterranea are being replaced by asexual individuals that are either conspecific or are from other species that are better adapted to the Mediterranean climate

The relationship of 3′UTR HLA-G14-bp insertion/deletion and +3142 C/G polymorphisms and soluble HLA-G expression with gynecological cancers: An updated meta-analysis

Objectives: Human leukocyte antigen-G (HLA-G) is implicated in several cancers and is considered to be an immune checkpoint regulator. We determined the association between polymorphisms in the 3' untranslated region of HLA-G and soluble HLA-G (sHLA-G) expression with gynecological cancers (GCs).Methods: A meta-analysis was conducted to examine the association between HLA-G14-bp insertion (I)/deletion (D) and +3142C/G polymorphism in GC and to evaluate sHLA-G expressionResults: We revealed a significant association between the +3142C/G polymorphism and invasive cervical cancer (ICC) based on the allelic model G versus C (odds ratio [OR] = 0.738, 95% confidence interval [CI] = 0.563-0.966, p = 0.027), dominant GG+GC versus CC (OR = 0.584, 95% CI = 0.395-0.862, p = 0.007), and codominant GG versus CC (OR = 0.527, 95% CI = 0.312-0.891, p = 0.017) models, suggesting that the G allele and GG genotype are protective against ICC. In gynecological precancerous patients with human papillomavirus (HPV) infection, we found that the 14-bp I/D under the codominant DD versus DI model (OR = 0.492, 95% CI = 0.241-1.004, p = 0.051) was of borderline signifi- cance. Soluble HLA-G levels were significantly higher in patients compared with healthy controls (standardized mean differences [SMD] = 1.434, 95% CI = 0.442-2.526, p = 0.005). Stratification by cancer type revealed that the sHLA-G levels were significantly increased in cervical cancer (SMD = 4.889, 95% CI = 0.468-9.310, p = 0.030) and in subjects of Asian ethnicity (SMD = 4.889, 95% CI = 0.467-9.309, p = 0.030).Conclusions: HLA-G14-bp I/D and +3142 C/G polymorphisms are associated with GC and HPV-associated cervical cancer. In addition, we found significantly increased sHLA-G levels in cancer patients. These results provide a basis for further studies in diagnostics and immunotherapy of GC

Survival pathways are differently affected by microgravity in normal and cancerous breast cells

Metazoan living cells exposed to microgravity undergo dramatic changes in morphological and biological properties, which ultimately lead to apoptosis and phenotype reprogramming. However, apoptosis can occur at very different rates depending on the experimental model, and in some cases, cells seem to be paradoxically protected from programmed cell death during weightlessness. These controversial results can be explained by considering the notion that the behavior of adherent cells dramatically diverges in respect to that of detached cells, organized into organoids-like, floating structures. We investigated both normal (MCF10A) and cancerous (MCF-7) breast cells and found that appreciable apoptosis occurs only after 72 h in MCF-7 cells growing in organoid-like structures, in which major modifications of cytoskeleton components were observed. Indeed, preserving cell attachment to the substrate allows cells to upregulate distinct Akt- and ERK-dependent pathways in MCF-7 and MCF-10A cells, respectively. These findings show that survival strategies may differ between cell types but cannot provide sufficient protection against weightlessness-induced apoptosis alone if adhesion to the substrate is perturbed

Quercetin directly promotes rabbit ovarian steroidogenesis

[EN] The bioflavonoid quercetin is a component of food with numerous biological effects, but its function in reproductive processes remains to be investigated. This study aimed to examine the direct action of quercetin on steroid hormone release in rabbit ovaries. We analysed the effect of quercetin (0, 1, 10, and 100 ng/mL) on cultured rabbit ovarian fragments. The release of progesterone (P4), testosterone (T) and estradiol (E2) were analysed by enzyme immunoassay. Quercetin promoted P4, T, and E2 release by rabbit ovarian fragments. These observations indicate that quercetin can directly stimulate rabbit ovarian steroidogenesis – an essential regulator of reproduction and fecundity. The application of dietary quercetin for control of rabbit reproduction is discussed.Sirotkin, A.; Štochmaľová, A.; Grossmann, R.; Alwasel, S.; Harrath, A. (2019). Quercetin directly promotes rabbit ovarian steroidogenesis. World Rabbit Science. 27(3):163-167. https://doi.org/10.4995/wrs.2019.11816163167273Anand D.A.V., Arulmoli R., Parasuraman S. 2016. Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn. Rev., 10: 84-89. https://doi.org/10.4103/0973-7847.194044Beazley K.E., Nurminskaya M. 2016. Effects of dietary quercetin on female fertility in mice: implication of transglutaminase 2. Reprod. Fertil. Dev., 28: 974-981. https://doi.org/10.1071/RD14155Boots A.W., Haenen G.R.M.M., Bast A. 2008. Health effect of quercetin: from antioxidant to nutraceutical. Eur. J. Pharmacol., 585: 325-337. https://doi.org/10.1016/j.ejphar.2008.03.008Chen C., Zhou, J.J., 2010a. Quercetin: A potential drug to reverse multidrug resistance. Life Sci., 87: 333-338. https://doi.org/10.1016/j.lfs.2010.07.004Chen Z.G., Luo L.L., Xu J.J., Zhuang X.L., Kong X.X., Fu Y.C., 2010b. Effects of plant polyphenols on ovarian follicular reserve in ageing rats. Biochem. Cell. 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Development of a sensitive enzyme immunoassay (EIA) for progesterone determination in unextracted bovine plasma using the second antibodytechnique. J. Steroid Biochem. Mol. Biol., 28: 623-627. https://doi.org/10.1016/0022-4731(87)90389-XRice S., Mason H.D., Whitehead S.A. 2006. Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cells. J. Steroid Biochem. Mol. Biol., 101: 216-225. https://doi.org/10.1016/j.jsbmb.2006.06.021Santini S.E., Basini G., Bussolati S., Grasselli F. 2009. The phytoestrogen quercetin impairs steroidogenesis and angiogenesis in swine granulosa cells in vitro. J. Biomed. Biotechnol., 2009: 419891. https://doi.org/10.1155/2009/419891Sharma A., Kashyap D., Sak K., Tuli H.S., Sharma A.K. 2018. Therapeutic charm of quercetin and its derivatives: a review of research and patents. Pharm. Pat. Anal., 7: 15-32. https://doi.org/10.4155/ppa-2017-0030Shu X., Hu X.J., Zhou S.Y., Xu C.L., Qiu Q.Q., Nie S.P., Xie M.Y. 2011. [Effect of quercetin exposure during the prepubertal period on ovarian development and reproductive endocrinology of mice]. Yao Xue Xue Bao, 46: 1051-1057.Sirotkin A.V. 2014. Regulators of ovarian functions. New York: Nova Science Publishers Inc. 194, ISBN 978-1-62948-574-4.Sirotkin A.V., Harrath A.H. 2014. Phytoestrogens and their effects. Eur J Pharmacol., 741: 230-236. https://doi.org/10.1016/j. ejphar.2014.07.057Sirotkin A.V., Chrenek P., Kolesarová A., Parillo F., Zerani M., Boiti C. 2014. Novel regulators of rabbit reproductive functions. Anim. Reprod. Sci., 148: 188-196. https://doi.org/10.1016/j.anireprosci.2014.06.001Sirotkin A.V., Kadasi A., Stochmalova A., Balazi A., Földesiová M., Makovicky P., Chrenek P., Harrath A.H. 2017. 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Microgravity Modifies the Phenotype of Fibroblast and Promotes Remodeling of the Fibroblast–Keratinocyte Interaction in a 3D Co-Culture Model

Microgravity impairs tissue organization and critical pathways involved in the cell– microenvironment interplay, where fibroblasts have a critical role. We exposed dermal fibroblasts to simulated microgravity by means of a Random Positioning Machine (RPM), a device that reproduces conditions of weightlessness. Molecular and structural changes were analyzed and compared to control samples growing in a normal gravity field. Simulated microgravity impairs fibroblast conversion into myofibroblast and inhibits their migratory properties. Consequently, the normal interplay between fibroblasts and keratinocytes were remarkably altered in 3D co-culture experiments, giving rise to several ultra-structural abnormalities. Such phenotypic changes are associated with down-regulation of α-SMA that translocate in the nucleoplasm, altogether with the concomitant modification of the actin-vinculin apparatus. Noticeably, the stress associated with weightlessness induced oxidative damage, which seemed to concur with such modifications. These findings disclose new opportunities to establish antioxidant strategies that counteract the microgravity-induced disruptive effects on fibroblasts and tissue organization

PCOS and inositols: controversial results and necessary clarifications. Basic differences between D-chiro and myo-inositol

Myo-Inositol (myo-Ins) and its phosphate derivatives—including inositol phosphates (InsPs), inositol pyrophosphates (IPPs) and phosphatidyl-inositol phosphate (PtdIns)—are credited to act as second messengers, which accumulate rapidly and transiently in response to external or endocrine signals, a phenomenon that allows signaling to be discrete and regulated (1, 2). Noticeably, inositol is involved in the transduction of several endocrine signals, including insulin (3, 4), thyroid hormones (5), gonadotropins (6), lipids with hormone-like activity (as prostaglandins) (7), and many other endocrine systems (8). Namely, in the last decade, a growing body of clinical and experimental research provided robust evidence about the efficiency of inositol in reversing a few clinical, metabolic, and endocrine features of the Polycystic Ovary Syndrome (PCOS). Myo-inositol, alone or in combination with its isomer D-Chiro-Inositol (D-Chiro-Ins), showed to exert a variable—albeit significant—effect in improving both symptoms and outcome in PCOS patients (9). Experimental and pilot clinical studies pointed out that a combination of both isomers could provide a reliable rationale for establishing a proper treatment strategy, as first suggested by Beemster’s seminal study (10, 11). However, the proper formula—i.e., the respective percentage of myo-Ins and D-Chiro-Ins—is still a matter of debate. In several cases, no conclusive insights can be obtained from clinical trials based on unclear rational design, limited number of recruited patients and variable formula composition and dosage(s). First, it is improper to compare clinical results from studies in which commercial nutraceutical formulas involve a wide range of concentrations (Table 1), with the myo-Ins/D-Chiro-Ins ratio varying implausibly from 0.4:1 to 104:1. Current commercial preparations also contain D-Chiro-Ins alone at concentrations reaching 600 mg that can be administered once or twice a day. Therefore, the daily dose of D-chiro-Ins, alone or with myo-Ins, ranges from low (less than 300 mg/die), medium (300–600 mg/die) and high (600–1,200 mg/die)

First case of childhood Takayasu arteritis with renal artery aneurysms

Takayasu arteritis is a large vessel systemic granulomatous vasculitis characterized by stenosis or obliteration of large and medium sized arteries. It commonly involves elastic arteries such as the aorta and its main branches. Renal artery involvement is rare and has not been reported in a child. We report a 12-year-old boy with Takayasu arteritis who developed severe hypertension, proteinuria, microscopic hematuria and renal dysfunction. Conventional angiography demonstrated aneurysms of both renal arteries and multiple microaneurysms of the superior mesenteric artery. This case report illustrates that the children with Takayasu arteritis can develop renal involvement resulting in hematuria, proteinuria and even renal failure