Primary Dengue and Long-Term Health Status in Madeira Island, Portugal: A Retrospective Questionnaire-Based Study.

Dengue is among the most important mosquito-borne viral diseases worldwide. Although its acute manifestations are well known, little is known about the long-term impact of dengue on the population's health status. Madeira Island experienced a single outbreak of autochthonous dengue from September 2012 to March 2013. To extend our knowledge about the clinical impact of the outbreak on this naive population, we applied an online questionnaire to 168 adults diagnosed with dengue at the time to characterize retrospectively their symptoms during the infection and to identify long-term manifestations, possibly triggered by dengue. The most frequent symptoms during the clinical period, reported by more than three-quarters of our participants, were fever, myalgia, extreme tiredness, and headaches, whereas vomiting, pruritus, nausea, retro-orbital pain, and arthralgia occurred in 35% to 50% of participants. In the 8 years after dengue, 61.5% of participants reported at least one recurrent previously nonexistent symptom, the most frequent being headaches, abundant hair loss, extreme tiredness, arthralgia, and myalgia, experienced by 25% to 35% of participants. Nearly 20% of the participants with persistent symptoms reported the onset of chronic illness in the 4 years after dengue, most frequently ophthalmological and autoimmune diseases (5.6% each), versus only 2.2% of chronic disease onset in participants without persistent symptoms. Our results suggest that the occurrence of persistent symptoms after primary dengue might be more frequent than anticipated and may persist for several years, having an impact on the health status and well-being of a considerable proportion of the infected population.

Altered expression of Sialyl Lewis X in experimental models of Parkinson's disease.

The mechanisms underlying neurodegeneration in Parkinson's disease (PD) are still not fully understood. Glycosylation is an important post-translational modification that affects protein function, cell-cell contacts and inflammation and can be modified in pathologic conditions. Although the involvement of aberrant glycosylation has been proposed for PD, the knowledge of the diversity of glycans and their role in PD is still minimal. Sialyl Lewis X (sLeX) is a sialylated and fucosylated tetrasaccharide with essential roles in cell-to-cell recognition processes. Pathological conditions and pro-inflammatory mediators can up-regulate sLeX expression on cell surfaces, which has important consequences in intracellular signalling and immune function. Here, we investigated the expression of this glycan using in vivo and in vitro models of PD. We show the activation of deleterious glycation-related pathways in mouse striatum upon treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin-based model of PD. Importantly, our results show that MPTP triggers the presentation of more proteins decorated with sLeX in mouse cortex and striatum in a time-dependent manner, as well as increased mRNA expression of its rate-limiting enzyme fucosyltransferase 7. sLeX is expressed in neurons, including dopaminergic neurons, and microglia. Although the underlying mechanism that drives increased sLeX epitopes, the nature of the protein scaffolds and their functional importance in PD remain unknown, our data suggest for the first time that sLeX in the brain may have a role in neuronal signalling and immunomodulation in pathological conditions. KEY MESSAGES: MPTP triggers the presentation of proteins decorated with sLeX in mouse brain. MPTP triggers the expression of sLeX rate-limiting enzyme FUT 7 in striatum. sLeX is expressed in neurons, including dopaminergic neurons, and microglia. sLeX in the brain may have a role in neuronal signalling and immunomodulation.

Flying under the radar - impact and factors influencing asymptomatic DENV infections.

The clinical outcome of DENV and other Flaviviruses infections represents a spectrum of severity that ranges from mild manifestations to severe disease, which can ultimately lead to death. Nonetheless, most of these infections result in an asymptomatic outcome that may play an important role in the persistent circulation of these viruses. Also, although little is known about the mechanisms that lead to these asymptomatic infections, they are likely the result of a complex interplay between viral and host factors. Specific characteristics of the infecting viral strain, such as its replicating efficiency, coupled with host factors, like gene expression of key molecules involved in the immune response or in the protection against disease, are among crucial factors to study. This review revisits recent data on factors that may contribute to the asymptomatic outcome of the world's widespread DENV, highlighting the importance of silent infections in the transmission of this pathogen and the immune status of the host.

Infection order outweighs the role of CD4+ T cells in tertiary flavivirus exposure.

The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection in macaques. We show that CD4+ depletion in DENV/ZIKV-primed animals followed by DENV resulted in dysregulated adaptive immune responses. We show a delay in DENV-specific IgM/IgG antibody titers and binding and neutralization in the DENV/ZIKV-primed CD4-depleted animals but not in ZIKV/DENV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in priming an early effective humoral response during sequential flavivirus infections. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding the complex flavivirus immune responses and for the development of effective flavivirus vaccines.

Phylogeography of Sub-Saharan Mitochondrial Lineages Outside Africa Highlights the Roles of the Holocene Climate Changes and the Atlantic Slave Trade.

Despite the importance of ancient DNA for understanding human prehistoric dispersals, poor survival means that data remain sparse for many areas in the tropics, including in Africa. In such instances, analysis of contemporary genomes remains invaluable. One promising approach is founder analysis, which identifies and dates migration events in non-recombining systems. However, it has yet to be fully exploited as its application remains controversial. Here, we test the approach by evaluating the age of sub-Saharan mitogenome lineages sampled outside Africa. The analysis confirms that such lineages in the Americas date to recent centuries-the time of the Atlantic slave trade-thereby validating the approach. By contrast, in North Africa, Southwestern Asia and Europe, roughly half of the dispersal signal dates to the early Holocene, during the "greening" of the Sahara. We elaborate these results by showing that the main source regions for the two main dispersal episodes are distinct. For the recent dispersal, the major source was West Africa, but with two exceptions: South America, where the fraction from Southern Africa was greater, and Southwest Asia, where Eastern Africa was the primary source. These observations show the potential of founder analysis as both a supplement and complement to ancient DNA studies.

Seasonal variation in microplastics and zooplankton abundances and characteristics: The ecological vulnerability of an oceanic island system.

The ingestion of microplastics (MPs - plastic particles <5 mm) by planktivorous organisms represents a significant threat to marine food webs. To investigate how seasonality might affect plastic intake in oceanic islands' ecosystems, relative abundances and composition of MPs and mesozooplankton samples collected off Madeira Island (NE Atlantic) between February 2019 and January 2020 were analysed. MPs were found in all samples, with fibres accounting for 89 % of the particles. MPs and zooplankton mean abundance was 0.262 items/m3 and 18.137 individuals/m3, respectively. Their monthly variations follow the seasonal fluctuation of environmental parameters, such as currents, chlorophyll-a concentration, sea surface temperature and precipitation intensity. A higher MPs/zooplankton ratio was recorded in the warm season (May-Oct), reaching 0.068 items/individual when considering large-sized particles (1000-5000 µm). This is the first study to assess the seasonal variability of MPs in an oceanic island system providing essential information respecting its ecological impact in pelagic environments.

Body mass index and gestational weight gain: relevance in gestational diabetes and outcomes - A retrospective cohort study.

Objective: To evaluate the influence of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on blood glucose levels at diagnosis of gestational diabetes mellitus (GDM) and obstetric/neonatal outcomes. Methods: Retrospective cohort study including 462 women with GDM and singleton pregnancy delivered in our institution between January 2015 and June 2018 and grouped according to BMI/GWG. Results: The diagnosis of GDM was more likely to be established in the 1st trimester (T) in women with obesity than in normal-weight (55.8% vs 53.7%, p = 0.008). BMI positively and significantly correlated with fasting plasma glucose (FPG) levels in the 1stT (rs = 0.213, p = 0.001) and 2ndT (rs = 0.210, p = 0.001). Excessive GWG occurred in 44.9% women with overweight and in 40.2% with obesity (p < 0.001). From women with obesity, 65.1% required pharmacological treatment (p < 0.001). Gestational hypertension (GH) was more frequent in women with obesity (p = 0.016). During follow-up, 132 cesareans were performed, the majority in mothers with obesity (p = 0.008). Of the 17 large-for-gestational-age (LGA) birthweight delivered, respectively 6 and 9 were offsprings of women with overweight and obesity (p = 0.019). Maternal BMI had a predictive value only for macrosomia [aOR 1.177 (1.006-1.376), p = 0.041]. BMI and GWG positively correlated with birthweight (rs = 0.132, p = 0.005; rs = 0.188, p = 0.005). Conclusion: Maternal obesity is related with a major probability of diagnosis of GDM in 1stT, fasting hyperglycemia in 2ndT and a more frequent need for pharmacological therapy. Pre-gestational obesity is associated with GH, cesarean delivery and fetal macrosomia.

Body mass index and gestational weight gain: relevance in gestational diabetes and outcomes - A retrospective cohort study

ABSTRACT Objective: To evaluate the influence of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) on blood glucose levels at diagnosis of gestational diabetes mellitus (GDM) and obstetric/neonatal outcomes. Subjects and methods: Retrospective cohort study including 462 women with GDM and singleton pregnancy delivered in our institution between January 2015 and June 2018 and grouped according to BMI/GWG. Results: The diagnosis of GDM was more likely to be established in the 1st trimester (T) in women with obesity than in normal-weight (55.8% vs 53.7%, p = 0.008). BMI positively and significantly correlated with fasting plasma glucose (FPG) levels in the 1stT (rs = 0.213, p = 0.001) and 2ndT (rs = 0.210, p = 0.001). Excessive GWG occurred in 44.9% women with overweight and in 40.2% with obesity (p < 0.001). From women with obesity, 65.1% required pharmacological treatment (p < 0.001). Gestational hypertension (GH) was more frequent in women with obesity (p = 0.016). During follow-up, 132 cesareans were performed, the majority in mothers with obesity (p = 0.008). Of the 17 large-for-gestational-age (LGA) birthweight delivered, respectively 6 and 9 were offsprings of women with overweight and obesity (p = 0.019). Maternal BMI had a predictive value only for macrosomia [aOR 1.177 (1.006-1.376), p = 0.041]. BMI and GWG positively correlated with birthweight (rs = 0.132, p = 0.005; rs = 0.188, p = 0.005). Conclusion: Maternal obesity is related with a major probability of diagnosis of GDM in 1stT, fasting hyperglycemia in 2ndT and a more frequent need for pharmacological therapy. Pre-gestational obesity is associated with GH, cesarean delivery and fetal macrosomia.

Biomolecular insights into North African-related ancestry, mobility and diet in eleventh-century Al-Andalus.

Historical records document medieval immigration from North Africa to Iberia to create Islamic al-Andalus. Here, we present a low-coverage genome of an eleventh century CE man buried in an Islamic necropolis in Segorbe, near Valencia, Spain. Uniparental lineages indicate North African ancestry, but at the autosomal level he displays a mosaic of North African and European-like ancestries, distinct from any present-day population. Altogether, the genome-wide evidence, stable isotope results and the age of the burial indicate that his ancestry was ultimately a result of admixture between recently arrived Amazigh people (Berbers) and the population inhabiting the Peninsula prior to the Islamic conquest. We detect differences between our sample and a previously published group of contemporary individuals from Valencia, exemplifying how detailed, small-scale aDNA studies can illuminate fine-grained regional and temporal differences. His genome demonstrates how ancient DNA studies can capture portraits of past genetic variation that have been erased by later demographic shifts-in this case, most likely the seventeenth century CE expulsion of formerly Islamic communities as tolerance dissipated following the Reconquista by the Catholic kingdoms of the north.

Effects of climate change and anthropogenic pressures in the water quality of a coastal lagoon (Ria Formosa, Portugal).

Understanding how climatic and anthropogenic drivers will influence coastal lagoons is fundamental to guarantee their preservation and sustainability. The Ria Formosa (coastal lagoon, South coast of Portugal) is a very important ecosystem that supports diverse economic activities in the region. The 3D coupled hydrodynamic-biogeochemical model SCHISM was validated and used to assess the influence of climate change and anthropogenic pressures on the water quality of the Ria Formosa. Five scenarios were simulated: reference scenario (S0), mean sea level rise (SLR) of 0.5 m (S1), increase of the air temperature of 1.68 °C (S2), increase of the outflow from the wastewater treatment plants (WWTP) by 50% (S3) and a combined scenario (S4). Results suggest that SLR of 0.5 m promotes an increase of 0.5-3 in the salinity near the area of influence of the WWTP. SLR decreases the inorganic nutrient concentrations in these areas by about 40-60%, due to an increase of the dilution. In contrast, the increase of the outflow from the WWTP by 50% increases the nutrients concentrations by about 20-40%. The increase of the air temperature alone by 1.68 °C increases the water temperature by 0-1 °C. The combined scenario suggests antagonist effects in the nutrient concentrations. Overall, the trophic index (TRIX) of the lagoon calculated for the scenarios exhibits only minor differences relative to the reference scenario, except in some areas near the WWTP discharges. In these areas, TRIX tends to increase with the increase of the outflow from the WWTP in scenario S3. These results provide further insight into the response of coastal lagoons, and the Ria Formosa in particular, to future changes and contribute to support their management.

First record of the pencil cardinal Epigonus denticulatus (Perciformes: Epigonidae) in the Azores archipelago.

The pencil cardinal Epigonus denticulatus is a small deep-water fish inhabiting continental slopes usually between 300 and 600 m depth. We report the first record of E. denticulatus in the Azores archipelago, where one specimen was found floating by fisherman off Faial island. Meristic and morphometric characters are in accordance with those reported for the species and molecular analyses further supported species identity. The record of E. denticulatus as a native species in the Azores increases the number of Epigonus species in the region to a total of three.

Brain functional connectivity changes by low back extension pain model in low back pain patients.

PURPOSE: Low back pain (LBP) is a common ailment in most developed countries. Because most cases of LBP are known as 'non-specific', it has been challenging to develop experimental pain models of LBP which reproduce patients' clinical pain. In addition, previous models have limited applicability in a steady-pain-state neuroimaging environment. Thus, this study aims to devise a low back pain model with a simple methodology to induce experimental LBP, which has similar pain properties to patients' clinical pain, and to apply the model in a steady-pain-state neuroimaging study. METHODS: Our low back extension (LBE) pain model was tested on 217 LBP patients outside the magnetic resonance imaging (MRI) scanner to determine the reproducibility of endogenous pain and the similarity to their own clinical pain (STUDY1), and applied in a steady-pain-state functional MRI study (47 LBP patients and 23 healthy controls) to determine its applicability (induced head motions and brain functional connectivity changes; STUDY2). RESULTS: By the LBE pain model, 68.2% of the LBP patients reported increased LBP with high similarity of sensations to their own clinical pain (STUDY1), and the head motions were statistically similar to and correlated with those in resting state (STUDY2). Furthermore, the LBE model altered brain functional connectivity by decreasing the default-mode and the sensorimotor networks, and increasing the salience network, which was significantly associated with the intensity of the induced pain. Conversely, the healthy controls showed increased somatosensory network (but not of the cognitive pain processing). CONCLUSION: Our investigations suggest that our LBE pain model, which increased LBP with high similarity to the LBP patients' own pain sensation and induced patient-specific brain responses with acceptable head motion, could be applied to neuroimaging studies investigating brain responses to different levels of endogenous LBP.

Desempenho escolar e comportamentos sociais em adolescentes / School performance and social behavior in adolescents

RESUMO Objetivo Analisar a associação entre o desempenho escolar, idade, gênero, classificação econômica e comportamentos sociais - capacidades e dificuldades - de acordo com o instrumento Questionário de Capacidades e Dificuldades - SDQ-Por (Strengths and Difficulties Questionnaire - SDQ), de escolares matriculados no ensino fundamental. Métodos A amostra foi composta por 124 adolescentes, de ambos os gêneros, matriculados no ensino fundamental II, com idades entre 11 e 14 anos. Todos os estudantes responderam ao Questionário de Caracterização dos Participantes e ao SDQ-Por e seus pais ou responsáveis, ao Critério de Classificação Econômica Brasil - CCEB. A análise do desempenho escolar foi determinada pela média aritmética simples das notas finais obtidas pelos estudantes. Os instrumentos utilizados para a coleta de dados foram viabilizados por meio do formulário on-line, Google Forms. Foram realizadas as análises descritiva e bivariada dos dados. Resultados A maioria dos participantes apresentou resultados adequados, em relação à análise do escore total do SDQ, que se refere às dificuldades, e à análise do comportamento pró- social. Quanto ao desempenho escolar, verificou-se que grande parte dos estudantes apresentou resultado muito bom ou excelente e que houve associação com a idade, o gênero e o ano escolar. Conclusão Os estudantes do gênero feminino, de 11 anos de idade, apresentaram melhor desempenho e os adolescentes com maiores dificuldades de comportamento estavam na categoria mais baixa de classificação do desempenho escolar.

ABSTRACT Purpose To analyze the association between school performance, age, gender, economic classification and social behaviors - strengths and difficulties - according to the Strengths and Difficulties Questionnaire - SDQ-Por, of students enrolled in junior high school. Methods The sample consisted of 124 adolescents of both genders, enrolled in junior high school, aged between 11 and 14 years of age. All students answered the Participant Characterization Questionnaire and the - SDQ-Por questionnaire and their parents or guardians answered the Brazil Economic Classification Criteria (CCEB). The school performance analysis was determined by simple arithmetic average of the final grades obtained by the students. The instruments used for data collection in this study were available through online forms in Google Forms. Descriptive and bivariate data analyzes were performed. Results Most participants presented adequate results regarding the analysis of the total SDQ score, which refers to the difficulties and the analysis of pro-social behavior. Regarding school performance, most of the participants presented very good or excellent results as well as an association with age, gender and school year of the students. Conclusion Female students, 11 years old, performed better and adolescents with larger behavioral difficulties were in the lowest category in the school performance classification.

Time elapsed between Zika and dengue virus infections affects antibody and T cell responses.

Zika virus (ZIKV) and dengue virus (DENV) are co-endemic in many parts of the world, but the impact of ZIKV infection on subsequent DENV infection is not well understood. Here we show in rhesus macaques that the time elapsed after ZIKV infection affects the immune response to DENV infection. We show that previous ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV. The time interval between ZIKV and subsequent DENV infection further affects the immune response. A mid-convalescent period of 10 months after ZIKV infection results in higher and more durable antibody and T cell responses to DENV infection than a short period of 2 months. In contrast, previous ZIKV infection does not affect DENV viremia or pro-inflammatory status. Collectively, we find no evidence of a detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the implementation of ZIKV vaccines that could also boost immunity against future DENV epidemics.

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy.

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD. Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells. Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.

Problemas relacionados con medicamentos que causan ingresos por urgencias en un hospital de alta complejidad.

OBJECTIVE: Determining hospital admissions prevalence associated with problems related to medicines in the emergency services of high complexity hospital; performing the pertinent pharmaceutical interventions. METHOD: Descriptive observational cross-sectional study. The medical records of the patients admitted to the emergency services were reviewed. Those that  reported hospitalization due to problems related to medication were selected.  These were classified according to the Third Consensus of Granada adaptation. A pharma-therapeutic profile was made to hospitalized patients; performing the  necessary pharmaceutical interventions to avoid future medication related  problems. RESULTS: 3.8% of patients were included in the study. The problems related to  medications had a preventability of 87.7% and the most frequent were those of  need with 42.2%. A pharma-therapeutic profile was done to hospitalized  patients (137). 150 pharmaceutical interventions were done, which had an  acceptance of 95.3%. The most intervened risk was administering an  unnecessary medication 62.7%. CONCLUSIONS: Lack of supervision and analysis of problems related to medication could cause therapeutic approach failure, therefore, health and life quality improvement of the patients is not achieve. The pharmaceutical chemist  plays a fundamental role in the health care of patients, helping to the prevention  and proper use of medicines. The Pharmaceutical Care program  proves that it provides an invaluable contribution to public health service by  improving the pharmacological safety of treatments, reducing costs and public  health problems.

Objetivo: Determinar la prevalencia de ingresos hospitalarios asociados a  problemas relacionados con medicamentos en los servicios de urgencias de un  hospital de alta complejidad, realizando las intervenciones farmacéuticas  pertinentes.Método: Estudio observacional descriptivo de corte transversal. Se revisaron las historias clínicas de pacientes que ingresaron en los servicios de urgencias,  seleccionando aquellas que reportaban ingresos por problemas relacionados con  medicamentos. Estas se clasificaron según la adaptación del Tercer Consenso de  Granada. Se realizó un perfil farmacoterapéutico a los pacientes hospitalizados y se establecieron las intervenciones farmacéuticas necesarias para evitar futuros  problemas relacionados con medicamentos.Resultados: El 3,8% de los pacientes fueron incluidos en el estudio. Los problemas relacionados con medicamentos tuvieron una evitabilidad del 87,7% y los más frecuentes fueron los de necesidad, con un 42,2%. Se realizó un perfil farmacoterapéutico a los pacientes hospitalizados (137) y se  llevaron a cabo 150 intervenciones farmacéuticas, las cuales fueron aceptadas  en un 95,3%. El riesgo más intervenido fue administrar un medicamento  innecesario (62,7%).Conclusiones: La falta de supervisión y análisis de problemas relacionados con  los medicamentos podría ocasionar el fracaso del abordaje terapéutico y la no  consecución de la mejoría de la salud y la calidad de vida de los pacientes. El  químico farmacéutico cumple un papel fundamental en el cuidado de la salud de  los pacientes, ayudando desde la prevención y el uso adecuado de los  medicamentos. El programa de Atención Farmacéutica demuestra que brinda un  aporte inestimable al servicio de la salud pública al mejorar la farmacoseguridad  de los tratamientos, disminuyendo costes y problemas de salud pública.

Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.

Novel insights into the antioxidant role of tauroursodeoxycholic acid in experimental models of Parkinson's disease.

Impaired mitochondrial function and generation of reactive oxygen species are deeply implicated in Parkinson's disease progression. Indeed, mutations in genes that affect mitochondrial function account for most of the familial cases of the disease, and post mortem studies in sporadic PD patients brains revealed increased signs of oxidative stress. Moreover, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor, leads to clinical symptoms similar to sporadic PD. The bile acid tauroursodeoxycholic acid (TUDCA) is an anti-apoptotic molecule shown to protect against MPTP-induced neurodegeneration in mice, but the mechanisms involved are still incompletely identified. Herein we used MPTP-treated mice, as well as primary cultures of mice cortical neurons and SH-SY5Y cells treated with MPP+ to investigate the modulation of mitochondrial dysfunction by TUDCA in PD models. We show that TUDCA exerts its neuroprotective role in a parkin-dependent manner. Overall, our results point to the pharmacological up-regulation of mitochondrial turnover by TUDCA as a novel neuroprotective mechanism of this molecule, and contribute to the validation of TUDCA clinical application in PD.

Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. Here, we show that tauroursodeoxycholic acid (TUDCA) prevents both 1-methyl-4-phenylpyridinium (MPP+)- and α-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain. Altogether, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD.