Melatonin administration during sexual maturation : influence on adult prostate histophysiology and protective role against damages caused by experimental diabetes

Orientador: Rejane Maira GóesTese (doutorado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: Dentre os efeitos decorrentes do diabetes na próstata de roedores estão à atrofia prostática, comprometimento da capacidade secretora, desequilíbrio na cinética epitelial, remodelação da matriz extracelular e mudanças morfofuncionais nas células estromais. Essas alterações têm sido associadas em grande parte à queda androgênica e à escassez insulínica. Entretanto, não se podem negligenciar os efeitos da hiperglicemia prolongada que ocasiona estresse oxidativo. A melatonina (MLT) possui propriedades antitumorais e é um potente antioxidante. Os indivíduos diabéticos apresentam comprometimento da síntese de MLT. Este estudo visou examinar se o tratamento de ratos com MLT desde o período pré-púbere até a idade adulta afeta a maturação da próstata ventral e os efeitos da administração prolongada de MLT na glândula. Também foi analisado o papel protetor da MLT nas alterações decorrentes do diabetes experimental em curto e longo prazo. A MLT foi administrada na água de beber (10?g/Kg peso corpóreo/dia) a partir da 5ª semana de idade até o final do experimento. Na 13ª semana de idade o diabetes foi induzido pela estreptozotocina (STZ, 40mg/Kg de peso corpóreo, ip). Os ratos foram eutanasiados na 14ª semana (1 semana de diabetes) e na 21ª semana de idade (2 meses de diabetes). Os resultados desse delineamento experimental (8 grupos/N = 10) resultaram em 3 capítulos. No 1º capítulo foram quantificados a atividade de catalase (CAT), glutationa S-tranferase (GST) e glutationa peroxidase (GPx) e peroxidação lipídica na próstata, testículo e epidídimo. O sistema antioxidante prostático foi o mais vulnerável ao diabetes, no qual houve aumento em curto prazo da GPx e da GST (p = 0.0186) e em longo termo da CAT e GST (p ? 0.001). A ingestão de MLT por ratos saudáveis aumentou em 47% a atividade da GPx epididimal. A MLT normalizou as desordens enzimáticas na próstata demonstrando a sua ação antioxidante mesmo em baixa dosagem. No 2º capítulo foram analisados os efeitos da MLT na maturação prostática e nas injúrias causadas pelo diabetes com ênfase na proliferação celular, apoptose e expressão do receptor de andrógeno (AR). Esse neurohormônio diminuiu em 10% a frequência de células AR-positivas epiteliais em ratos saudáveis no início da vida adulta. O tratamento com MLT a ratos diabéticos de longo prazo diminuiu os índices apoptóticos e aumentou a proliferação celular, devido à normalização da testosterona circulante encontrada nesses animais. A influência in vitro da MLT em células tumorais andrógeno-dependentes (22Rv1), independentes (PC3) e células epiteliais humanas (PNTA1) em condições normais (NC) e hiperglicêmicas (HG) foram avaliadas. As células 22Rv1 foram as mais sensíveis à MLT. Esse hormônio diminuiu os índices mitóticos das linhagens 22Rv1 e PNTA após curta pré-incubação em meio hiperglicêmico. Porém, os níveis proliferativos das células PC3 foram favorecidos pela MLT em condições HG. Assim como nos animais diabéticos de longo prazo, a MLT favoreceu a sobrevivência das células PC3 em condições hiperglicêmicas. No 3º capítulo foi analisado se o diabetes induzido por STZ favorece o estabelecimento de lesões malignas e pré-malignas na próstata. Também foi avaliado se a MLT evita o desenvolvimento dessas alterações histopatológicas nos animais diabéticos e se ingestão desse hormônio afeta o componente epitelial e estromal de animais sadios. A MLT foi mais influente na histologia prostática quando administrada durante a puberdade. Esse tratamento atenuou a atrofia epitelial e das células musculares lisas, restaurou a distribuição colagênica e reduziu a incidência de neoplasias intraepiteliais (PIN) de alto grau, prostatite e atrofia proliferativa inflamatória (PIA) nos ratos diabéticos. Entretanto, a baixa dosagem MLT não impediu a ocorrência do carcinoma microinvasivo. O diabetes induzido por STZ permite o estudo da incidência e progressão tumoral em condições de hiperglicemia, porém não se podem descartar os efeitos específicos da droga tais como o aumento da metilação que ocorre nos animais diabéticosAbstract: The prostate response to diabetes in rodents includes atrophy, impairment of secretory activity, imbalance in epithelial kinetics, extracellular matrix remodeling and morphofuncional changes of stromal cells. These alterations are associated to the drop of androgen levels and insulin scarcity. However, the effects of prolonged hyperglycemia, which leads to oxidative stress, cannot be neglected. Melatonin (MLT) has antitumor and antioxidant actions. Diabetic individuals have a malfunction of MLT synthesis. This investigation aimed to examine if MLT treatment to rats since prepubertal period until adulthood affects ventral prostate maturation and the effects of prolonged administration of this hormone in the gland. The protective action of MLT on alterations caused by short- and long-term diabetes was also analyzed. MLT was provided in drinking water (10 ?g/kg b.w./day) since 5th week of age until the end of experiment. Diabetes was induced by streptozotocin (STZ, 40mg/kg b.w., ip) in 13 weeks old rats. The rats were euthanized with 14 (one-week diabetes) or 21 weeks old (two months diabetes). The results of the above experimental design (8 groups/N =10) were divided in 3 chapters. In the first chapter, the activity of catalase (CAT), gluthatione S-transferase (GST) and glutathione peroxidase (GPx) and lipid peroxidation levels were assessed in prostate, testis and epidydimis. Prostate antioxidant system was the most vulnerable to diabetic condition, in which there was an increase of GPx and GST (p = 0.0186) activities at short-term, and CAT and GST (p ? 0.001) at long-term. MLT normalized the enzymatic disorders in prostate, proving its antioxidant property even at low dosage. In the second chapter, the effects of MLT in prostate maturation and injuries caused by experimental diabetes were studied regarding cell proliferation, apoptosis and androgen receptor expression (AR). This neurohormone decreased by 10% frequency of the epithelial AR-positive cells in healthy rats at early adult life. The treatment with MLT to long-term diabetic rats decreased the apoptotic index and increased the cell proliferation, and this was due to the normalization of circulating testosterone levels found in these animals. The in vitro effect of MLT on androgen-dependent (22Rv1), independent (PC3) tumor cells and human epithelial cells (PNTA1) under normal (NC) and hyperglycemic (HG) conditions were evaluated. 22Rv1 cells were the most sensitive to MLT. This hormone diminished the mitosis of 22Rv1 and PNTA1 after short pre-incubation in hyperglycemic medium. Similar to the long-term diabetic animals, MLT favored the survival of PC3 cells in hyperglycemic condition. In the third chapter, we investigated if STZ-induced diabetes favors the establishment of malignant and pre-malignant lesions in prostate. The effectiveness of MLT in avoiding these histopathological alterations in diabetic animals and if its ingestion by healthy rats affects the epithelial and stromal compartiments were evaluated. MLT was more influent in prostatic histology when administered during puberty. This treatment attenuated the atrophy of epithelium and smooth muscle cells, restored the collagen distribution and reduced the incidence of high-grade intraepithelial neoplasia (PIN), prostatitis and proliferative inflammatory atrophy (PIA). Meanwhile, low doses of MLT did not preclude the occurrence of microinvasive carcinoma. The STZ-induced diabetes allows the assessment of tumor incidence and progression under hyperglycemic conditions, but the secondary effects of STZ cannot be discarded, as the increase of DNA methylation found in diabetic animalsDoutoradoBiologia CelularDoutora em Biologia Funcional e Molecula

correction an epr study of ampullosporin a a medium length peptaibiotic in bicelles and vesicles

Correction for 'An EPR study of ampullosporin A, a medium-length peptaibiotic, in bicelles and vesicles' by Marco Bortolus et al., Phys. Chem. Chem. Phys., 2016, 18, 749–760

Digital for Heritage and Museums: Design-Driven Changes and Challenges

In the recent decade, cultural institutions have increasingly embraced digital technologies as key resources for accomplishing their mission and innovating their cultural activities. In the present work, we attempt to disentangle through a design-driven and multidisciplinary approach the challenges brought by digital transformation in the cultural heritage sector. A diversified research team has thus been involved to include scholars with different backgrounds around the common phenomenon of investigation of Digital (Cultural) Heritage, under the Design Think Thank project. The Introduction is followed by a Methodological section, which outlines the approach to select and review case studies from the exploratory literature for producing a state-of-the-art report and delineates the methodology to map the main user behaviours and needs in the digital experience of CH throughout the value chain. The research team identified three relevant and major themes for the investigation which are addressed in the Literature Review Section through the lenses of design research and practices; simultaneously, design knowledge emerges to have an agency in the transformation. The following section tries to triangulate the results from the literature review, and the mapping of users and stakeholders throughout the cultural institutions value chain, to track and highlight their role and interest in changing heritage panorama. The contribution of the present work wishes to consolidate the results gathered in the first phases of the TT, providing the design community of academics and practitioners with a theoretical contribution about digital changes and challenges of heritage and museums based on a design perspective

Light-Induced TripletTriplet Electron Resonance Spectroscopy

We present a new technique, light-induced triplet-triplet electron resonance spectroscopy (LITTER), which measures the dipolar interaction between two photoexcited triplet states, enabling both the distance and angular distributions between the two triplet moieties to be determined on a nanometer scale. This is demonstrated for a model bis-porphyrin peptide that renders dipolar traces with strong orientation selection effects. Using simulations and density functional theory calculations, we extract distance distributions and relative orientations of the porphyrin moieties, allowing the dominant conformation of the peptide in a frozen solution to be identified. LITTER removes the requirement of current light-induced electron spin resonance pulse dipolar spectroscopy techniques to have a permanent paramagnetic moiety, becoming more suitable for in-cell applications and facilitating access to distance determination in unmodified macromolecular systems containing photoexcitable moieties. LITTER also has the potential to enable direct comparison with Förster resonance energy transfer and combination with microscopy inside cells

Randomized Clinical Trial on Ivermectin versus Thiabendazole for the Treatment of Strongyloidiasis

Strongyloidiasis is the infection caused by the worm Strongyloides stercoralis. Due to its peculiar life cycle Strongyloides may remain indefinitely in the host, if not effectively cured. Although the disease is usually mild, in case of weakening of the host's immune defenses the worm may invade virtually all organs and tissues (disseminated strongyloidiasis, almost invariably fatal). The treatment must then reach the goal of the complete elimination of the parasite. Small size clinical trials showed similar, high efficacy of the two drugs ivermectin (used as a single dose) and thiabendazole (used twice daily for two consecutive days). All trials used as the criterion for cure the absence of larvae in stool exams. The latter however may easily miss the infection, falsely suggesting that the infection has been cured. This trial, using a test detecting specific Strongyloides antibodies as an additional and more sensitive diagnostic tool, confirms previous reports: the two drugs have similar efficacy but ivermectin is better tolerated and is therefore the first choice. However the cure rate was lower than 70% for the standard, single dose. The authors then conclude that a larger, multi center trial is needed to find the optimal dose schedule of ivermectin

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: LaMPO RCT

OBJECTIVES: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. METHODS: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. RESULTS: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. CONCLUSIONS: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain

Limit on Bs0B^0_s oscillation using a jet charge method

A lower limit is set on the B_{s}^{0} meson oscillation parameter \Delta m_{s} using data collected from 1991 to 1994 by the ALEPH detector. Events with a high transverse momentum lepton and a reconstructed secondary vertex are used. The high transverse momentum leptons are produced mainly by b hadron decays, and the sign of the lepton indicates the particle/antiparticle final state in decays of neutral B mesons. The initial state is determined by a jet charge technique using both sides of the event. A maximum likelihood method is used to set a lower limit of \, \Delta m_{s}. The 95\% confidence level lower limit on \Delta m_s ranges between 5.2 and 6.5(\hbar/c^{2})~ps^{-1} when the fraction of b quarks from Z^0 decays that form B_{s}^{0} mesons is varied from 8\% to 16\%. Assuming that the B_{s}^{0} fraction is 12\%, the lower limit would be \Delta m_{s} 6.1(\hbar/c^{2})~ps^{-1} at 95\% confidence level. For x_s = \Delta m_s \, \tau_{B_s}, this limit also gives x_s 8.8 using the B_{s}^{0} lifetime of \tau_{B_s} = 1.55 \pm 0.11~ps and shifting the central value of \tau_{B_s} down by 1\sigma

Measurement of the Bs0^0_s lifetime and production rate with Ds−l+^-_s l^+ combinations in Z decays

The lifetime of the \bs meson is measured in approximately 3 million hadronic Z decays accumulated using the ALEPH detector at LEP from 1991 to 1994. Seven different \ds decay modes were reconstructed and combined with an opposite sign lepton as evidence of semileptonic \bs decays. Two hundred and eight \dsl candidates satisfy selection criteria designed to ensure precise proper time reconstruction and yield a measured \bs lifetime of \mbox{\result .} Using a larger, less constrained sample of events, the product branching ratio is measured to be \mbox{\pbrresult