Potential of marine compounds in the treatment of neurodegenerative diseases: a review.

Neurodegenerative diseases (ND) are characterized, especially, by the progressive loss of neurons, resulting in neuropsychomotor dysfunctions. Even with a high prevalence, NDs are treated with drugs that alleviate the symptoms of patients, but which develop adverse events and still do not inhibit the progression of the disease. Thus, within a new pharmacological perspective, this review aimed to verify the therapeutic potential of natural compounds of marine origin against ND. For this, an integrative review was carried out, according to the PRISMA methodology, which included steps such as: search, pre-selection and inclusion of articles. The results described revealed species such as Acaudina malpodioides, Holothuria scabra and Xylaria sp., which presented important evidence in relation to Alzheimer's, reducing the generation of ROS, presenting neuroprotective effects and reducing the concentration of Aß peptide. Regarding Parkinson's disease (PD), another example of ND, the bioactive compounds from Holothuria scabra and Xylaria sp., showed to be able to reduce the degeneration of dopaminergic neurons, reduce the deposition of alpha synuclein and reduce the formation of Mutant Huntingtin protein (Mhtt). The other marine compounds and bioactive substances are also described in this review. In conclusion, the evaluated studies indicate that compounds of marine origin emerge as a promising source of bioactive compounds, revealing an important therapeutic potential for the treatment of ND.

Endoparasite community of anurans from an altitudinal rainforest enclave in a Brazilian semiarid area.

In the present study, we aimed to describe the composition of endoparasites associated with anurans from an altitudinal rainforest enclave in northeastern Brazil. Additionally, we tested if microhabitat use influences endoparasite abundance and richness, as well as the hypothesis that larger frogs tend to be more parasitized. We sampled 306 individuals from 25 anuran species that were necropsied and analysed using a stereomicroscope. The total endoparasite prevalence was 79.08%, with a parasitic community consisting of 46 taxa. Overall, we found the common pattern described for Neotropical amphibians, which is the predominance of generalist and direct-cycle parasites. Twenty new host records and two possible new parasite species were found, highlighting the importance of this type of inventory. We also observed that microhabitat use was associated with a significant difference in parasite richness between groups, in which arboreal and terrestrial species, and aquatic and arboreal species contributed to these differences. Moreover, larger frogs tended to be more parasitized regarding only an interspecific view. Our results suggest that parasite richness is directly related to infection cycle and how the host exploits its habitat.

Mild-to-moderate COVID-19 impact on the cardiorespiratory fitness in young and middle-aged populations.

The goal of the present study was to compare pulmonary function test (PFT) and cardiopulmonary exercise test (CPET) performance in COVID-19 survivors with a control group (CG). This was a cross-sectional study. Patients diagnosed with COVID-19, without severe signs and symptoms, were evaluated one month after the infection. Healthy volunteers matched for sex and age constituted the control group. All volunteers underwent the following assessments: i) clinical evaluation, ii) PTF; and iii) CPET on a cycle ergometer. Metabolic variables were measured by the CareFusion Oxycon Mobile device. In addition, heart rate responses, peak systolic and diastolic blood pressure, and perceived exertion were recorded. Twenty-nine patients with COVID-19 and 18 healthy control subjects were evaluated. Surviving patients of COVID-19 had a mean age of 40 years and had higher body mass index and persistent symptoms compared to the CG (P<0.05), but patients with COVID-19 had more comorbidities, number of medications, and greater impairment of lung function (P<0.05). Regarding CPET, patients surviving COVID-19 had reduced peak workload, oxygen uptake (V̇O2), carbon dioxide output (V̇CO2), circulatory power (CP), and end-tidal pressure for carbon dioxide (PETCO2) (P<0.05). Additionally, survivors had depressed chronotropic and ventilatory responses, low peak oxygen saturation, and greater muscle fatigue (P<0.05) compared to CG. Despite not showing signs and symptoms of severe disease during infection, adult survivors had losses of lung function and cardiorespiratory capacity one month after recovery from COVID-19. In addition, cardiovascular, ventilatory, and lower limb fatigue responses were the main exercise limitations.

Mild-to-moderate COVID-19 impact on the cardiorespiratory fitness in young and middle-aged populations

The goal of the present study was to compare pulmonary function test (PFT) and cardiopulmonary exercise test (CPET) performance in COVID-19 survivors with a control group (CG). This was a cross-sectional study. Patients diagnosed with COVID-19, without severe signs and symptoms, were evaluated one month after the infection. Healthy volunteers matched for sex and age constituted the control group. All volunteers underwent the following assessments: i) clinical evaluation, ii) PTF; and iii) CPET on a cycle ergometer. Metabolic variables were measured by the CareFusion Oxycon Mobile device. In addition, heart rate responses, peak systolic and diastolic blood pressure, and perceived exertion were recorded. Twenty-nine patients with COVID-19 and 18 healthy control subjects were evaluated. Surviving patients of COVID-19 had a mean age of 40 years and had higher body mass index and persistent symptoms compared to the CG (P<0.05), but patients with COVID-19 had more comorbidities, number of medications, and greater impairment of lung function (P<0.05). Regarding CPET, patients surviving COVID-19 had reduced peak workload, oxygen uptake (V̇O2), carbon dioxide output (V̇CO2), circulatory power (CP), and end-tidal pressure for carbon dioxide (PETCO2) (P<0.05). Additionally, survivors had depressed chronotropic and ventilatory responses, low peak oxygen saturation, and greater muscle fatigue (P<0.05) compared to CG. Despite not showing signs and symptoms of severe disease during infection, adult survivors had losses of lung function and cardiorespiratory capacity one month after recovery from COVID-19. In addition, cardiovascular, ventilatory, and lower limb fatigue responses were the main exercise limitations.

Reliability and validity of six-minute step test in patients with heart failure.

Exercise intolerance is the hallmark consequence of advanced chronic heart failure (HF). The six-minute step test (6MST) has been considered an option for the six-minute walk test because it is safe, inexpensive, and can be applied in small places. However, its reliability and concurrent validity has still not been investigated in participants with HF with reduced ejection fraction (HFrEF). Clinically stable HFrEF participants were included. Reliability and error measurement were calculated by comparing the first with the second 6MST result. Forty-eight hours after participants underwent the 6MST, they were invited to perform a cardiopulmonary exercise test (CPET) on a cycle ergometer. Concurrent validity was assessed by correlation between number of steps and peak oxygen uptake (V̇O2 peak) at CPET. Twenty-seven participants with HFrEF (60±8 years old and left ventricle ejection fraction of 41±6%) undertook a mean of 94±30 steps in the 6MST. Intra-rater reliability was excellent for 6MST (ICC=0.9), with mean error of 4.85 steps and superior and inferior limits of agreement of 30.6 and -20.9 steps, respectively. In addition, strong correlations between number of steps and CPET workload (r=0.76, P<0.01) and peak V̇O2 (r=0.71, P<0.01) were observed. From simple linear regression the following predictive equations were obtained with 6MST results: V̇O2 peak (mL/min) = 350.22 + (7.333 × number of steps), with R2=0.51, and peak workload (W) = 4.044 + (0.772 × number of steps), with R2=0.58. The 6MST was a reliable and valid tool to assess functional capacity in HFrEF participants and may moderately predict peak workload and oxygen uptake of a CPET.

Reliability and validity of six-minute step test in patients with heart failure

Exercise intolerance is the hallmark consequence of advanced chronic heart failure (HF). The six-minute step test (6MST) has been considered an option for the six-minute walk test because it is safe, inexpensive, and can be applied in small places. However, its reliability and concurrent validity has still not been investigated in participants with HF with reduced ejection fraction (HFrEF). Clinically stable HFrEF participants were included. Reliability and error measurement were calculated by comparing the first with the second 6MST result. Forty-eight hours after participants underwent the 6MST, they were invited to perform a cardiopulmonary exercise test (CPET) on a cycle ergometer. Concurrent validity was assessed by correlation between number of steps and peak oxygen uptake (V̇O2 peak) at CPET. Twenty-seven participants with HFrEF (60±8 years old and left ventricle ejection fraction of 41±6%) undertook a mean of 94±30 steps in the 6MST. Intra-rater reliability was excellent for 6MST (ICC=0.9), with mean error of 4.85 steps and superior and inferior limits of agreement of 30.6 and -20.9 steps, respectively. In addition, strong correlations between number of steps and CPET workload (r=0.76, P<0.01) and peak V̇O2 (r=0.71, P<0.01) were observed. From simple linear regression the following predictive equations were obtained with 6MST results: V̇O2 peak (mL/min) = 350.22 + (7.333 × number of steps), with R2=0.51, and peak workload (W) = 4.044 + (0.772 × number of steps), with R2=0.58. The 6MST was a reliable and valid tool to assess functional capacity in HFrEF participants and may moderately predict peak workload and oxygen uptake of a CPET.

Epidemiologic analysis of salivary gland tumors over a 10-years period diagnosed in a northeast Brazilian population.

BACKGROUND: Salivary gland tumors (SGT) correspond to a heterogeneous group of lesions with variable biological behavior. The present study aimed to determine the distribution and demographic findings of salivary gland neoplasms in a northeast Brazilian population. MATERIAL AND METHODS: A retrospective descriptive cross-sectional study was performed. A total of 588 cases of SGT were diagnosed between 2006 and 2016 of 4 pathology services in the state of Sergipe, Brazil. All cases were reviewed, and data such as sex, age, anatomical location, and histopathological diagnosis were collected. RESULTS: A total of 470 (79.9%) tumors were benign and 118 (20.1%) were malignant. The majority of the patients were females (n=328, 55.8%) with an overall female:male ratio of 1.2:1. The major salivary glands were affected more than the minor glands (69.5% vs. 30.5%). Pleomorphic adenoma (n=419, 71.3%) and mucoepidermoid carcinoma (n=29, 4.9%) were the most frequent benign and malignant tumors, respectively. In addition, both benign and malignant tumors occurred more frequently in the parotid gland (n=300, 51%, p<0.05). CONCLUSIONS: The epidemiologic profile and clinical characteristics of SGT were similar to those described in other countries and other regions of Brazil. Epidemiological studies of SGT help to understand their clinical and pathological features and are essential to establish the proper management and prognosis.

Assessing sociodemographic differences in human papillomavirus vaccine impact studies in the United States: a systematic review using narrative synthesis.

OBJECTIVES: Sociodemographic disparities in the incidence and mortality of human papillomavirus (HPV)-associated conditions have been well documented in the pre-HPV vaccine era. It is still unknown if the introduction of routine vaccination has been effective in reducing these prevaccine era inequalities. The purpose of this review was to determine the utilization of sociodemographic variables to assess for disparities in population-level HPV vaccine impact research and to evaluate the current evidence for disparities in the reduction of HPV-associated conditions after vaccine introduction in the United States (US). STUDY DESIGN: A systematic review of the literature from January 2007 through March 2018 was carried out to identify studies evaluating the impact HPV vaccines have had on the rates of HPV infection, genital warts, and cervical dysplasia (cervical intraepithelial neoplasia grades 1+) in the US. An in-depth review was then performed to synthesize these data and to assess the way prior studies have reported and evaluated for potential disparities in the vaccine's impact within various racial, ethnic, and/or socio-economic subgroups of the population. METHODS: Vaccine impact studies measure the change in the population-level burden of disease prelicensure versus postlicensure of the vaccine. We systematically searched PubMed/Medline and Embase, combining search terms related to the HPV vaccine, sentinel surveillance, and HPV-associated conditions. Eligible studies were those with population-level, postvaccine introduction data that were conducted in the US. Finally, a cited reference search was conducted for all included articles using the Web of Science platform that accesses three major citation indexes: Science Citation Index, Social Sciences Citation Index, and Arts and Humanities Citation Index. This allowed us to screen not only the articles that were cited by our final collection of studies but also the articles that used our selected studies as one of their references. The study protocol is registered in PROSPERO (#CRD42018107579). RESULTS: Overall, 23 of the 4139 references retrieved assessed the population-level impact of HPV vaccines between January 1, 2007, and March 29, 2018. Among these, 13 (57%) reported sociodemographic data. Only two articles reported stratified results by sociodemographic factors, thereby allowing assessment for potential disparate impact. One of these studies described differences in the impact of the vaccine by race, ethnicity, and income. CONCLUSION: Although approximately half of the studies that assessed the impact of the HPV vaccine measured sociodemographic characteristics, few presented results in a way that allowed for the identification of potential differences in impact between the relevant subgroups of the population. Determining to what extent, if any, vaccines are reducing known sociodemographic disparities is an important public health priority and an essential step in developing immunization strategies that are beneficial for all.

Validation of the two-minute step test in obese with comorbibities and morbidly obese patients.

Cardiopulmonary fitness assessment is a valuable resource to obtain quantitative indicators of an individual's physical performance. The cardiopulmonary exercise test (CPX), considered the gold standard test for this evaluation, is costly and difficult to be accessed by the general population. In order to make this evaluation more accessible, and to better reflect the performance of daily life activities, alternative tests were proposed. Morbidly obese patients present limitations that impair physical performance assessment and could benefit from a test of shorter duration, provided it is validated. This observational study aimed to validate the two-minute step test (2MST) as a tool to evaluate functional capacity (FC) in obese with comorbidities and morbidly obese patients, compared the 2MST with CPX as a measure of physical performance, and developed a predictive equation to estimate peak oxygen uptake (VO2) in the 2MST. The CPX and the 2MST were performed and metabolic and ventilatory parameters were recorded in 31 obese individuals (BMI>35 kg/m2). Pearson correlation and multiple linear regression analyses were performed to evaluate the peak VO2 best predictors. Bland-Altman analysis was performed to assess the agreement between the two methods. Peak VO2 measured by CPX and 2MST showed a strong correlation (r=0.70, P<0.001) and there was a moderate correlation between peak VO2 of the 2MST and the number of up-and-down step cycles (UDS) (r=0.55; P=0.01). The reference equation obtained was: VO2 (mL·kg-1·min-1) = 13.341 + 0.138 × total UDS - (0.183 × BMI), with an estimated standard error of 1.3 mL·kg-1·min-1. The 2MST is a viable, practical, and easily accessible test for FC. UDS and BMI can predict peak VO2 satisfactorily.

Pyrethrum extract encapsulated in nanoparticles: Toxicity studies based on genotoxic and hematological effects in bullfrog tadpoles.

The environment receives about 2.7 kg.ha-1 annually of pesticides, used in crop production. Pesticides may have a negative impact on environmental biodiversity and potentially induce physiological effects on non-target species. Advances in technology and nanocarrier systems for agrochemicals led to new alternatives to minimize these impacts, such as nanopesticides, considered more efficient, safe and sustainable. However, it is important to evaluate the risk potential, action and toxicity of nanopesticides in aquatic and terrestrial organisms. This study aims to evaluate genotoxic and hematological biomarkers in bullfrog tadpoles (Lithobates catesbeianus) submitted to acute exposure (48 h) to pyrethrum extract (PYR) and solid lipid nanoparticles loaded with PYR. Results showed increased number of leukocytes during acute exposure, specifically eosinophils in nanoparticle-exposed groups, and basophil in PYR-exposed group. Hematological analysis showed that PYR encapsulated in nanoparticles significantly increased the erythrocyte number compared to the other exposed groups. Data from the comet assay indicated an increase in frequency of the classes that correspond to more severe DNA damages in exposed groups, being that the PYR-exposed group showed a high frequency of class-4 DNA damage. Moreover, erythrocyte nuclear abnormalities were triggered by short-time exposure in all treatments, which showed effects significantly higher than the control group. These results showed genotoxic responses in tadpoles, which could trigger cell death pathways. Concluding, these analyses are important for applications in assessment of contaminated aquatic environments and their biomonitoring, which will evaluate the potential toxicity of xenobiotics, for example, the nanoparticles and pyrethrum extract in frog species. However, further studies are needed to better understand the effects of nanopesticides and botanical insecticides on non-target organisms, in order to contribute to regulatory aspects of future uses for these systems.

Validation of the two-minute step test in obese with comorbibities and morbidly obese patients

Cardiopulmonary fitness assessment is a valuable resource to obtain quantitative indicators of an individual's physical performance. The cardiopulmonary exercise test (CPX), considered the gold standard test for this evaluation, is costly and difficult to be accessed by the general population. In order to make this evaluation more accessible, and to better reflect the performance of daily life activities, alternative tests were proposed. Morbidly obese patients present limitations that impair physical performance assessment and could benefit from a test of shorter duration, provided it is validated. This observational study aimed to validate the two-minute step test (2MST) as a tool to evaluate functional capacity (FC) in obese with comorbidities and morbidly obese patients, compared the 2MST with CPX as a measure of physical performance, and developed a predictive equation to estimate peak oxygen uptake (VO2) in the 2MST. The CPX and the 2MST were performed and metabolic and ventilatory parameters were recorded in 31 obese individuals (BMI>35 kg/m2). Pearson correlation and multiple linear regression analyses were performed to evaluate the peak VO2 best predictors. Bland-Altman analysis was performed to assess the agreement between the two methods. Peak VO2 measured by CPX and 2MST showed a strong correlation (r=0.70, P<0.001) and there was a moderate correlation between peak VO2 of the 2MST and the number of up-and-down step cycles (UDS) (r=0.55; P=0.01). The reference equation obtained was: VO2 (mL·kg-1·min-1) = 13.341 + 0.138 × total UDS - (0.183 × BMI), with an estimated standard error of 1.3 mL·kg-1·min-1. The 2MST is a viable, practical, and easily accessible test for FC. UDS and BMI can predict peak VO2 satisfactorily.

Chlorogenic acid improves the quality of boar semen subjected to cooled storage at 15°C.

The aim of this study was to investigate the effect of chlorogenic acid (ChA) in boar semen stored at 15°C. Twelve ejaculates were processed into insemination doses at different concentrations of ChA (0.0, 1.5, 3.0, 4.0 and 6.0 mg/ml) or vitamin E (200 µl/ml) as positive control. Semen was analysed after 0, 24 and 72 hr of storage. ChA improved (p < .05) sperm motility, acrosome integrity and mitochondrial activity in all periods of storage. Furthermore, after 24 hr of storage, ChA above 1.5 mg/ml supported the sperm viability until 120 min after reheating (p < .05). Both ChA and vitamin E were similarly efficient in increasing the antioxidant capacity of semen, reducing the malondialdehyde levels before and after 72 hr of storage (p < .05). However, with 72 hr of storage, ChA at 3.0 mg/ml improved the mitochondrial activity over vitamin E (p < .05). In conclusion, results suggest that the concentration of 3.2 mg/ml of ChA is the best for semen stored for up to 24 hr. However, for semen stored for a longer period, 6.0 mg/ml or more should be used.

Functional dimorphic enantiostyly in monomorphic enantiostylous species of the subtribe Cassiinae (Fabaceae-Caesalpinioideae).

Monomorphic enantiostylous species produce flowers with a displacement of the style to the left (L) or right (R) on the same individual, and may exhibit different dynamics for the production of these floral types, which may influence levels of selfing. We investigated the production dynamics of L and R floral types in seven species and a variety of monomorphic enantiostylous species of the genera Senna and Chamaecrista. Our hypothesis was that most species present similar proportions of floral morphs each day. Individuals were classified daily over a period of 7 days according to the functional status, i.e. the proportion of floral morphs as functionally L, R or reciprocal (REC, i.e. similar proportions of the two floral morphs), and also according to the number of consecutive days in which they exhibited the same functional status. All species presented low daily flower production. Most species had individuals classified as functionally R, L and REC, and tend to repeat the same functional status over a few days, although they may change functional status during the flowering period. All species exhibited individuals that were classified as functionally reciprocal when both the daily and total number of flowers produced over 7 days was considered. The occurrence of different functional status has not yet been reported in the literature for enantiostylous species. The distinct strategies observed in the dynamics of floral morph production seemed likely to minimise geitonogamy and to favour cross-pollination between individuals (xenogamy).

Brain insulin signalling, glucose metabolism and females' reproductive aging: A dangerous triad in Alzheimer's disease.

Alzheimer's disease (AD) constitutes a major socioeconomic challenge due to its disabling features and the rise in prevalence (especially among (peri)menopausal women and type 2 diabetes patients). The precise etiopathogenesis of AD remains poorly understood. Importantly, its neurodegenerative perspective has been challenged towards a more "systemic" view. Amyloid-ß (Aß) and hyperphosphorylated Tau protein (P-Tau) (the main AD neuropathological features) affect and are affected by peripheral and brain insulin signalling dysfunction, leading to glucose dysmetabolism, synaptic loss and AD-related cognitive deficits. This may be anticipated and exacerbated by the progressive loss of estrogen (and interactions, e.g., with insulin) during females' aging, increasing their risk for AD, especially during menopause. Under this perspective, we aimed to discuss the recent findings (and controversies) behind the peripheral view of AD, and the role for insulin deficits and brain glucose dysmetabolism in such diseased brain. We also focused on the metabolic shift and the putative effects of gender (especially during midlife/perimenopause) herein. We finally discussed AD as the potential "type 3 diabetes", and the therapeutic potential of restoring brain insulin levels or glucose energy metabolism via administration of intranasal insulin and use of ketogenic diets. In sum, AD appears to lie on an intricate crosstalk between age-related metabolic, hormonal and specific genetic changes that challenge its traditional view. Hence, clarification of AD risk factors (besides aging and gender) and pathophysiological mechanisms will allow to establish accurate preventive strategies, biomarkers and more efficient drugs - all urgent medical needs in our increasingly aged societies. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Helminths Infecting the Cat-eyed Snake Leptodeira Annulata Linnaeus 1758 (Squamata: Dipsadidae) in a Semiarid Region of Brazil.

Snakes have diverse feeding and living habits, being exposed to a variety of endoparasite communities. However, more studies are still necessary to document these relationships. We examined 18 specimens of the cat-eyed snake Leptodeira annulata from a semi-arid region in Northeast Brazil. Eight taxa of parasites were found, with higher prevalence of cystacanths (Acanthocephala). Five nematode species (Hexametra boddaertii, Oswaldocruzia sp., Oxyascaris sp., Physaloptera sp. and Raillietnema spectans) and the pentastome Raillietiella furcocerca represent a new parasitism record for the host studied. Our results also showed that L. annulata could act as paratenic host for acanthocephalans. These results contribute to the knowledge of the helminth fauna of L. annulata.

The mediational role of distracting stimuli in emotional word recognition.

Emotions are considered distractions that often prompt subsequent actions. In this way, the aim of this work was to examine the role of distracting stimuli on the relationship of RT and accuracy. In order to do that, a word recognition task was carried out in which emotional valence was manipulated. More precisely, a mediational model, testing how changes in distracting stimuli mediate RT predicting accuracy across emotional conditions, was carried out. The results suggest that changes in task demands should distract from the secondary task to the extent that these task demands implicate and affect accuracy. Moreover, the distracting task seems to mediate between accuracy and the target task under emotional stimuli, showing the negative distracting condition to be the most remarkable effect. Furthermore, neutral distracting latencies did not affect accuracy. Understanding the mechanisms by which emotion impairs cognitive functions has important implications in several fields, such as affective disorders. However, the effects of emotion on goal-directed cognitive processing remain unclear.

The mediational role of distracting stimuli in emotional word recognition

Abstract Emotions are considered distractions that often prompt subsequent actions. In this way, the aim of this work was to examine the role of distracting stimuli on the relationship of RT and accuracy. In order to do that, a word recognition task was carried out in which emotional valence was manipulated. More precisely, a mediational model, testing how changes in distracting stimuli mediate RT predicting accuracy across emotional conditions, was carried out. The results suggest that changes in task demands should distract from the secondary task to the extent that these task demands implicate and affect accuracy. Moreover, the distracting task seems to mediate between accuracy and the target task under emotional stimuli, showing the negative distracting condition to be the most remarkable effect. Furthermore, neutral distracting latencies did not affect accuracy. Understanding the mechanisms by which emotion impairs cognitive functions has important implications in several fields, such as affective disorders. However, the effects of emotion on goal-directed cognitive processing remain unclear.

Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer's-Disease Related Pathology.

Multiple lines of evidence state a major role for mitochondrial dysfunction in sporadic Alzheimer's disease (AD) etiopathogenesis. However, the molecular mechanism(s) triggered by mitochondrial deficits that lead to neurodegeneration remain elusive. Herein, we propose a new mechanism by which mitochondrial loss of potential leads to a dysfunction in autophagy/mitophagy due to the overactivation of SIRT2, a tubulin deacetylase that regulates microtubule network acetylation, and provide insights into the association between metabolism, phosphorylation, and Aß aggregation. We observed an increase in SIRT2 levels and a decrease in the acetylation of lys40 of tubulin in AD cells containing patient mtDNA as well as in AD brains. SIRT2 loss of function either with AK1 (a specific SIRT2 inhibitor) or by SIRT2 knockout recovers microtubule stabilization and improves autophagy, favoring cell survival through the elimination of toxic Aß oligomers. Our data provide strong evidence for a functional role of tubulin acetylation on autophagic vesicle traffic and mitochondria degradation. We propose that SIRT2 inhibition may improve microtubule assembly thus representing a valid approach as disease-modifying therapy for AD.

Middle-Aged Diabetic Females and Males Present Distinct Susceptibility to Alzheimer Disease-like Pathology.

Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones' function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sex-associated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and non-obese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting. Albeit the high levels of plasma estradiol and progesterone observed in middle-aged control females suggested that they were still under their reproductive phase, some gonadal dysfunction might be already occurring in T2D ones, hence, anticipating their menopause. Moreover, the higher blood and lower brain cholesterol levels in female rats suggested that its dysfunctional uptake into the brain cortex may also hamper peripheral estrogen uptake and/or its local brain steroidogenic metabolism. Despite the massive drop in IGF-1 levels in females' brains, particularly upon T2D, they might have developed some compensatory mechanisms towards the maintenance of estrogen, IGF-1, and insulin receptors function and of the subsequent Akt- and ERK1/2-mediated signaling. These may ultimately delay the deleterious AD-like brain changes (including oxidative damage to lipids and DNA, amyloidogenic processing of amyloid precursor protein and increased tau protein phosphorylation) associated with T2D and/or age (reproductive senescence) in female rats. By demonstrating that differential sex steroid hormone profiles/action may play a pivotal role in brain over T2D progression, the present study reinforces the need to establish sex-specific preventive and/or therapeutic approaches and an appropriate time window for the efficient treatment against T2D and AD.