Alzheimer's disease (AD) is the most common form of dementia in old age. Cognitive impairment in AD may be partially due to overall hypometabolism. Indeed, AD is characterized by an early ...region-specific decline in glucose utilization and by mitochondrial dysfunction, which have deleterious consequences for neurons through increased production of reactive oxygen species (ROS), ATP depletion and activation of cell death processes. In this article, we provide an overview of the alterations on energetic metabolism occurring in AD. First, we resume the evidences that link the 'metabolic syndrome' with increased risk for developing AD and revisit the major changes occurring on both extra-mitochondrial and mitochondrial metabolic pathways, as revealed by imaging studies and biochemical analysis of brain and peripheral samples obtained from AD patients. We also cover the recent findings on cellular and animal models that highlight mitochondrial dysfunction as a fundamental mechanism in AD pathogenesis. Recent evidence posits that mitochondrial abnormalities in this neurodegenerative disorder are associated with changes in mitochondrial dynamics and can be induced by amyloid-beta (Aβ) that progressively accumulates within this organelle, acting as a direct toxin. Furthermore, Aβ induces activation of glutamate N-methyl-D-aspartate receptors (NMDARs) and/or excessive release of calcium from endoplasmic reticulum (ER) that may underlie mitochondrial calcium dyshomeostasis thereby disturbing organelle functioning and, ultimately, damaging neurons. Throughout the review, we further discuss several therapeutic strategies aimed to restore neuronal metabolic function in cellular and animal models of AD, some of which have reached the stage of clinical trials.
Schistosomiasis affects million people and its control is widely dependent on a single drug, praziquantel. Computational chemistry has led to the development of new tools that predict molecular ...properties related to pharmacological potential. We conducted a theoretical study of the imizadole alkaloids of Pilocarpus microphyllus (Rutaceae) with schistosomicidal properties. The molecules of epiisopiloturine, epiisopilosine, isopilosine, pilosine, and macaubine were evaluated using theory models (B3lyp/SDD, B3lyp/6-31+G(d,p), B3lyp/6-311++G(d,p)). Absorption, distribution, metabolization, excretion, and toxicity (ADMET) predictions were used to determine the pharmacokinetic and pharmacodynamic properties of the alkaloids. After optimization, the molecules were submitted to molecular docking calculations with the purine nucleoside phosphorylase, thioredoxin glutathione reductase, methylthioadenosine phosphorylase, arginase, uridine phosphorylase, Cathepsin B1 and histone deacetylase 8 enzymes, which are possible targets of Schistosoma mansoni. The results showed that B3lyp/6-311++G(d,p) was the optimal model to describe the properties studied. Thermodynamic analysis showed that epiisopiloturine and epiisopilosine were the most stable isomers; however, the epiisopilosine ligand achieved a superior interaction with the enzymes studied in the molecular docking experiments, which corroborated the results of previous experimental studies on schistosomiasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Non-small cell lung cancer (NSCLC) is still diagnosed at late stages in Brazil. The availability of newer treatment options has changed patient management, however, few real-world data have been ...published since then. This is a population-based retrospective cohort study that aims to evaluate the characteristics of stage III/IV NSCLC patients and their journey in the Brazilian private healthcare system. Patients aged ≥18 years, residing in Brazil who had their first medical appointment between 2016 and 2018 were included in the study. The sociodemographic and clinical characteristics of the patients and time intervals of interest were described. A total of 10,394 patients were analyzed. The majority of the patients were male (58.5%) with a median age of 64.0 (IQR = 58.0 – 71.0) years. In relation to characteristics of the disease, most of the tumors were characterized as adenocarcinomas (52.3%) and diagnosed at stage IV (72.2%). Most patients arrived at the hospital with an established NSCLC diagnosis, while 45.7% were diagnosed at the first medical appointment in the hospital or later. For patients who were diagnosed at the first medical appointment or later, a median interval of 15.0 (IQR = 6.0 – 33.0) days was observed between the first medical appointment and the diagnosis. The first treatment was given after a median of 25.0 (IQR = 6.0 – 49.0) days after diagnosis for patients without a prior diagnosis, and 57.0 (IQR: 33.0 – 98.0) days for patients with a prior diagnosis. The most common treatments were chemotherapy alone (33.8%), chemotherapy combined with radiotherapy (21.5%), radiotherapy alone (13.1%), adjuvant or neoadjuvant treatment (9.3%), surgery (3.3%), and immunotherapy (0.7%; alone or combined). At the end of follow-up (September, 2020), 52.3% of the patients had died. Despite having more treatment options in the private sector, data show that there is a need to improve access to technologies.
The objective of the present study was to describe the relationship of seminal plasma and total sperm cell proteins with the semen freezability parameters of Guzerat bulls. Thirteen bulls were ...subjected to breeding soundness evaluation. Semen samples were collected, cryopreserved, and then post-thawing sperm kinetics were assessed, where high ( = 7) and low ( = 6) freezability groups were defined. Seminal plasma and total sperm proteins from the 2 groups were separated by 2-dimensional SDS-PAGE, and spots were identified by mass spectrometry. Semen parameters post-cryopreservation were as follows in the high and low freezability groups, respectively: mean total motility, 52.4 ± 20.5 and 13.7 ± 3.9; percentage of normal sperm, 89.0 ± 2.6 and 64.7 ± 14.0; and reactivity of hypo-osmotic swelling test, 38.9 ± 4.7 and 13.6 ± 3.7. Three seminal plasma proteins (osteopontin-K, DNase γ precursor, and DNASE1L3) and 6 proteins from sperm cells (acrosome formation-associated factor isoform 2, annexin A1, disintegrin and metalloproteinase domain-containing protein 2, dihydrolipoyl dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase) were highly expressed ( < 0.05) in the high freezability group. Another 6 seminal plasma proteins (acrosin inhibitor 1, glutathione peroxidase 3, metalloproteinase inhibitor 2, ephrin-A1, annexin A1, and platelet-activating factor acetylhydrolase) were significantly higher ( < 0.05) in the low freezability group. We described the associations of seminal plasma and sperm cell proteins with post-thawing sperm viability of Guzerat bulls raised in a typical semiarid environment. Such associations indicate that specific seminal plasma proteins more abundant in bulls of low semen freezability may be a response to an early oxidative stress that is not detected by conventional prefreezing semen evaluation. Moreover, specific sperm proteins were more associated with good freezability. The results presented here can serve as guidelines for future research aiming to develop better extenders and/or to improve bull semen selection for cryopreservation.
Identifying the strategies used to promote critical thinking (CT) during undergraduate education in nursing courses.
Systematic review.
Five electronic databases were searched without language, ...publication time or geographic filters.
A systematic review of the literature. Including experimental studies that considered at least one teaching strategy to promote critical thinking of undergraduate students in Nursing courses. The search for studies occurred in three phases: title and summary review, complete text and implementation of a clinical form of selection according to predetermined criteria. All included studies were assessed for quality through a classification tool for experimental studies.
Six studies were selected. The results were grouped into three key themes: an evaluation of the quality of the selected studies, characterization of the studies and the strategies used to promote critical thinking. All selected studies were in English, with significant conceptual similarity of Critical Thinking and dominance in choosing the approached theme during strategies in clinical nursing education with an emphasis on the nursing process.
The most widely used teaching intervention was Problem-Based Learning. Nursing education mediated by strategies that stimulate CT is considered a positive difference in undergraduate curriculums.
•The strategy most used was the problem based learning.•Incorporating strategies that promote critical thinking requires pedagogical reflection of the teacher.•Educational institutions consider the strategies that encourage critical thinking.
To establish prevention strategies, recording the prevalence of foot injuries within a herd should be the starting point in determining the risk factors involved in digital diseases. This study aimed ...to assess the prevalence of claw disorders in lactating Jersey cows raised in a semi-confinement system.
Five hundred and eighty-four digits were examined from 73 lactating Jersey cows. The lameness score system was used to assess each cow while walking and on standing position, and digital lesions were evaluated with the cows restrained in a hydraulic cattle chute.
The prevalence of digital lesions was 93.1%. Among the 68 affected cows, only 21 were lame. Of the 584 digits examined, 970 lesions were recorded, corresponding to 13.3% lesions per cow and 1.66% injuries per digit. Forty-eight cows (65.7%) had lesions in all digits, and 92.8% of digits had at least one lesion. Lesions in digits of fore limbs were more common (55.3%) (p<0.0001) than those of hind limbs (44.7%). Foot injuries in medial digits of the fore limbs were more prevalent (56.8%) (p<0.001) than in the lateral digits (43.2%). The lesions' occurrence was similar in both medial and lateral digits of the hind limbs (p=0.8347). The primary diseases observed were heel horn erosion (53.8%), white line disease (19.3%), and double sole (12.4%), which together accounted for 92.4% and 84.9% of foot disorders diagnosed in the fore and hind limbs, respectively. Other digital diseases occurred less frequently.
The prevalence of foot disorders in lactating Jersey cows raised in semi-confinement systems was high. This could be due to the lack of preventive trimming, infectious diseases, and nutritional problems.
Mesoporous silica, SBA-15, decorated with different amounts of TiO2 (anatase) were prepared by a sol-gel method followed by hydrothermal treatment and calcination, in the presence of a soft template, ...copolymer Pluronic 123. Tetraethyl orthosilicate (TEOS) was used as the SiO2 precursor and commercially available TiO2 anatase nanoparticles as the supported photocatalyst. The materials were characterized by transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDS), N2 adsorption-desorption isotherms, raman spectroscopy, ground state diffuse reflectance (GSDR), laser induced luminescence (LIL) and X-ray photoelectron spectroscopy (XPS). The zeta potentials of the pure SBA-15, TiO2/SBA-15 substrate and the commercial anatase sample were monitored through a complete range of pH values. All the nanomaterials developed in this work were studied in terms of their photoactivity in the UV range and in the visible range, separately. In the first case, hydroxyl radicals (OH) were confirmed to be the key active oxidizers in the photodegradation of the pesticide amicarbazone in aqueous medium. On the other hand, in the visible range, and following a dye sensitization process via a fluorescent rhodamine-like dye, two different mechanisms could be identified for the formation of the superoxide radical anion, O2−.
Display omitted
•This work presents a full characterization of TiO2 decorated SBA-15 particles.•The structural and photochemical evaluation of the materials was performed.•The formation of both hydroxyl and superoxide anion radicals was assessed.•A fluorescent dye was used as the surface probe in visible excitation conditions.•Amicarbazone was used as the model contaminant following UVA excitation.
Poor wear resistance of titanium is a major concern since relative movements due to the cyclic loads in body environment cause wear between the bone and the implant material leading to detachment of ...the wear debris and release of metal ions due to the simultaneous action of corrosion and wear, defined as tribocorrosion. In order to increase the tribocorrosion resistance, Grade 2 Ti matrix 24vol% B4C particle reinforced composites were processed by hot pressing. Corrosion behaviour was investigated by electrochemical impedance spectroscopy and potentiodynamic polarization in 9g/L NaCl solution at body temperature. Tribocorrosion tests were performed under open circuit potential, as well as under potentiodynamic polarization using a reciprocating ball-on-plate tribometer. Results suggested that the addition of B4C particles provided lower tendency to corrosion and lower corrosion kinetics under sliding, along with significantly reduced wear loss, mainly due to the load carrying effect given by the reinforcement particles.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid ...plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.
SIRT3 is a major regulator of mitochondrial acetylome. Here we show that SIRT3 is neuroprotective in Huntington's disease (HD), a motor neurodegenerative disorder caused by an abnormal expansion of ...polyglutamines in the huntingtin protein (HTT). Protein and enzymatic analysis revealed that increased SIRT3 is a signature in several HD models, including human HD brain, which is regulated by oxidative species. While loss of SIRT3 further aggravated the oxidative phenotype, antioxidant treatment regularized SIRT3 levels. SIRT3 overexpression promoted the antioxidant effect in cells expressing mutant HTT, leading to enhanced mitochondrial function and balanced dynamics. Decreased Fis1 and Drp1 accumulation in mitochondria induced by SIRT3 expression favored mitochondrial elongation, while the SIRT3 activator ε-viniferin improved anterograde mitochondrial neurite transport, sustaining cell survival. Notably, SIRT3 fly-ortholog dSirt2 overexpression in HD flies ameliorated neurodegeneration and extended lifespan. These findings provide a link between oxidative stress and mitochondrial dysfunction hypotheses in HD and offer an opportunity for therapeutic development.
Display omitted
•SIRT3 levels and activity are consistently increased in HD models and human HD brain.•Increased SIRT3 is a stress response to abnormal HD oxidative metabolism.•Loss of SIRT3 aggravates HD oxidative phenotype.•SIRT3 activation in HD models regularizes mitochondrial metabolism and dynamics.•dSirt2/SIRT3 overexpression in HD flies alleviate neurodegeneration.
PDF
