Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease

The accumulation of misfolded proteins in neurons, leading to the formation of cytoplasmic and nuclear aggregates, is a common theme in age-related neurodegenerative diseases, possibly due to disturbances of the proteostasis and insufficient activity of cellular protein clearance pathways. Lithium is a well-known autophagy inducer that exerts neuroprotective effects in different conditions and has been proposed as a promising therapeutic agent for several neurodegenerative diseases. We tested the efficacy of chronic lithium 10.4 mg/kg) treatment in a transgenic mouse model of Machado-Joseph disease, an inherited neurodegenerative disease, caused by an expansion of a polyglutamine tract within the protein ataxin-3. A battery of behavioral tests was used to assess disease progression. In spite of activating autophagy, as suggested by the increased levels of Beclin-1, Atg7, and LC3II, and a reduction in the p62 protein levels, lithium administration showed no overall beneficial effects in this model concerning motor performance, showing a positive impact only in the reduction of tremors at 24 weeks of age. Our results do not support lithiumchronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).FCT -Fundação para a Ciência e a Tecnologia(SFRH/BD/51059/2010

Anti-inflammatory and analgesic potential of hydrolyzed extract of Agave sisalana Perrine ex Engelm., Asparagaceae

The hemolytic, anti-inflammatory and antinociceptive properties from hydrolyzed extract Agave sisalana Perrine ex Engelm., Asparagaceae (HEAS) was evaluated classic inflammation models. Male Swiss mice and male Wistars rats received HEAS (500 mg/kg) in two administration p.o. and i.p. in saline solution 0.9%. The acid hydrolysis inhibited the hemolytic action of saponins due to the retreat of side chain sugar. The treatment of the ear induced oedema by xylene with HEAS significantly reduced in two routes 13 +/- 1.5 and 10 +/- 0.63 mg, respectively, p.o. and i.p., in comparison with controls 27 1.5 saline and 13.5 +/- 1.2 AAS. The HEAS also diminished edema induced by carrageenin 43 +/- 1.58 mg (p.o.) and 17 +/- 1.26 mg (i.p.), when compared with control groups 52 +/- 1.58 mg (saline) and 10.05 +/- 1.58 (indomethacin). HEAS showed analgesic effects in abdominal constrictions 30.7% (p.o.), 88.7% (i.p.) comparable to that produced by (AAS) 70.6%. However in granuloma cotton pellet a chronic model of inflammation just the i.p. pathway decreased granulomatous tissue (20.4 +/- 1.32 mg) compared with controls 30.5 +/- 2.53 mg (saline) and 20.2 +/- 2.18 mg (dexamethasone). These data suggest that HEAS has anti-inflammatory and analgesic activity on acute and chronic processes.20337638

Citalopram reduces aggregation of ATXN3 in a YAC transgenic mouse model of Machado-Joseph disease

Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is a fatal polyglutamine disease with no disease-modifying treatment. The selective serotonin reuptake inhibitor citalopram was shown in nematode and mouse models to be a compelling repurposing candidate for Machado-Joseph disease therapeutics. We sought to confirm the efficacy of citalopram to decrease ATXN3 aggregation in an unrelated mouse model of Machado-Joseph disease. Four-week-old YACMJD84.2 mice and non-transgenic littermates were given citalopram 8 mg/kg in drinking water or water for 10 weeks. At the end of treatment, brains were collected for biochemical and pathological analyses. Brains of citalopram-treated YACMJD84.2 mice showed an approximate 50% decrease in the percentage of cells containing ATXN3-positive inclusions in the substantia nigra and three examined brainstem nuclei compared to controls. No differences in ATXN3 inclusion load were observed in deep cerebellar nuclei of mice. Citalopram effect on ATXN3 aggregate burden was corroborated by immunoblotting analysis. While lysates from the brainstem and cervical spinal cord of citalopram-treated mice showed a decrease in all soluble forms of ATXN3 and a trend toward reduction of insoluble ATXN3, no differences in ATXN3 levels were found between cerebella of citalopram-treated and vehicle-treated mice. Citalopram treatment altered levels of select components of the cellular protein homeostatic machinery that may be expected to enhance the capacity to refold and/or degrade mutant ATXN3. The results here obtained in a second independent mouse model of Machado-Joseph disease further support citalopram as a potential drug to be repurposed for this fatal disorder.This work was funded by Becky Babcox Research Fund/pilot research award G015617, University of Michigan to M.C.C. and NINDS/NIH R01NS038712 to H.L.P. The work performed at the University of Minho was funded by the European Regional Development Funds (FEDER), through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This article was developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER. This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to P.M.) and [EXPL/BIM-MEC/ 0239/2012] (to A.T.C.); by FCT through the project [POCI-01-0145- FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to P.M.); by National Ataxia Foundation (to P.M. and to A.T.C.); and by Ataxia UK (to P.M.). S.D.S. and A.T.C. were supported by fellowships from FCT, SFRH/BD/ 78388/2011 and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa and EU/FSE

Prostaglandin E2 Signals Through PTGER2 to Regulate Sclerostin Expression

The Wnt signaling pathway is a robust regulator of skeletal homeostasis. Gain-of-function mutations promote high bone mass, whereas loss of Lrp5 or Lrp6 co-receptors decrease bone mass. Similarly, mutations in antagonists of Wnt signaling influence skeletal integrity, in an inverse relation to Lrp receptor mutations. Loss of the Wnt antagonist Sclerostin (Sost) produces the generalized skeletal hyperostotic condition of sclerosteosis, which is characterized by increased bone mass and density due to hyperactive osteoblast function. Here we demonstrate that prostaglandin E2 (PGE2), a paracrine factor with pleiotropic effects on osteoblasts and osteoclasts, decreases Sclerostin expression in osteoblastic UMR106.01 cells. Decreased Sost expression correlates with increased expression of Wnt/TCF target genes Axin2 and Tcf3. We also show that the suppressive effect of PGE2 is mediated through a cyclic AMP/PKA pathway. Furthermore, selective agonists for the PGE2 receptor EP2 mimic the effect of PGE2 upon Sost, and siRNA reduction in Ptger2 prevents PGE2-induced Sost repression. These results indicate a functional relationship between prostaglandins and the Wnt/β-catenin signaling pathway in bone

Medidas orofaciais em nipobrasileiros após crescimento puberal

OBJETIVO: descrever medidas orofaciais em nipobrasileiros após crescimento puberal e verificar diferenças entre medidas de mulheres negras, brancas e nipobrasileiras. MÉTODO: a casuística foi composta de 90 sujeitos japoneses ou descendentes de japoneses, sem histórico de miscigenação, ambos os sexos, entre 20 e 50 anos, sem queixas ou atendimentos fonoaudiológicos atuais ou prévios em motricidade orofacial, sem tratamento ortodôntico atual e sem alteração cognitiva. As medidas avaliadas foram: lábio superior, lábio inferior, filtro, terço superior da face, terço médio da face, terço inferior da face, lados da face, abertura máxima de boca e abertura máxima de boca com a língua na papila. O instrumento utilizado foi o paquímetro eletrônico digital da marca Jomarca. Os dados foram comparados com os achados na literatura referentes às mulheres negras e brancas. RESULTADOS: os dados coletados mostraram homogeneidade entre as medidas; os valores para todas as medidas foram maiores nos homens, com relevância estatística positiva. As diferenças mais significantes entre as negras, brancas e nipobrasileiras foram: terço superior e filtro das nipobrasileiras menor do que de negras e brancas. Para o terço médio não houve diferença estatística significante. O lábio superior das nipobrasileiras é maior do que das brancas e o lábio inferior das nipobrasileiras menor do que das negras. Lados da face sem diferenças estatísticas. CONCLUSÃO: foi possível verificar que as médias das medidas foram sempre maiores nos homens, que houve relações significantes entre algumas medidas orofaciais e que houve diferença estatisticamente significante entre as estruturas das brancas, negras e nipobrasileiras.PURPOSE: to describe orofacial measurements in nipobrazilians individuals after pubertal growth and to verify the differences among black, white and nipobrazilians women measures. METHOD: the sample was composed by 90 Asian, Japanese and Japanese descendants, with no history of miscegenation, both genders, from 20 to 50 years old, with no complaints, current or previous speech therapy in orofacial mycology, not being orthodontic treated and with no cognitive impairment. The evaluated measurements were: upper lip, lower lip, philtrum, upper face, middle face, lower face, sides of the face, mouth aperture and maximum aperture of mouth with the tongue in the papilla. The instrument used was a Jomarca digital caliper. The data were compared to black and white women findings from the literature. RESULTS: collected data showed homogeneity among the measurements; the values for all measures were higher in men, with positive statistical relevance. The most significant differences among black, white and nipobrazilians were: smaller nipobrazilian's upper third and philtrum than in black and white women. There was no statistically significant difference for the middle third. Nipobrazilians upper lip was bigger than in white women and nipobrazilians lower lip was smaller than in black woman. Face's sides did not show statistical differences among ethnic groups. CONCLUSION: in the studied sample it was possible to verify that the averages of the measurements were always higher in men, there were significant associations among some orofacial measurements and there was statistically significant difference among the structures of white, black and nipobrazilians women