Recovery of rare earth elements (Nd3+ and Dy3+) by using carbon-based adsorbents from spent tire rubber.

Two samples of spent tire rubber (rubber A and rubber B) were submitted to thermochemical conversion by pyrolysis process. A450, B450 and A900, B900 chars were obtained from rubber A and rubber B at 450 °C and 900 °C, respectively. The chars were then applied as recovery agents of Nd3+ and Dy3+ from aqueous solutions in mono and bicomponent solutions, and their performance was benchmarked with a commercial activated carbon. The chars obtained at 900 °C were the most efficient adsorbents for both elements with uptake capacities around 30 mg g-1. The chars obtained at 450 °C presented uptake capacities similar to the commercial carbon (≈ 11 mg g-1). A900 and B900 chars presented a higher availability of Zn ions that favored the ion exchange mechanism. It was found that Nd3+ and Dy3+ were adsorbed as oxides after Zn was released from silicate structures (Zn2SiO4). A900 char was further selected to be tested with Nd/Dy binary mixtures and it was found a trend to adsorb a slightly higher amount of Dy3+ due to its smaller ionic radius. The uptake capacity in bicomponent solutions was generally higher than for single component solutions due to the higher driving force triggered by the higher concentration gradient.

Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado-Joseph Disease.

Mitochondrial dysfunction has been described in many neurodegenerative disorders; however, there is less information regarding mitochondrial deficits in Machado-Joseph disease (MJD), a polyglutamine (polyQ) disorder caused by CAG repeat expansion in the ATXN3 gene. In the present study, we characterized the changes in mitochondrial function and biogenesis markers in two MJD models, CMVMJD135 (MJD135) transgenic mice at a fully established phenotype stage and tetracycline-regulated PC6-3 Q108 cell line expressing mutant ataxin-3 (mATXN3). We detected mATXN3 in the mitochondrial fractions of PC6-3 Q108 cells, suggesting the interaction of expanded ATXN3 with the organelle. Interestingly, in both the cerebella of the MJD135 mouse model and in PC6-3 Q108 cells, we found decreased mitochondrial respiration, ATP production and mitochondrial membrane potential, strongly suggesting mitochondrial dysfunction in MJD. Also, in PC6-3 Q108 cells, an additional enhanced glycolytic flux was observed. Supporting the functional deficits observed in MJD mitochondria, MJD135 mouse cerebellum and PC6-3 Q108 cells showed reduced cytochrome c mRNA and protein levels. Overall, our findings show compromised mitochondrial function associated with decreased cytochrome c levels in both cell and animal models of MJD.

Uncovering the Early Events Associated with Oligomeric Aß-Induced Src Activation.

Soluble Aß1-42 oligomers (AßO) are formed in the early stages of Alzheimer's disease (AD) and were previously shown to trigger enhanced Ca2+ levels and mitochondrial dysfunction via the activation of N-methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AßO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aß1-42 on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AßO induce H2O2-dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca2+ rise, enhanced cytosolic and subsequent mitochondrial H2O2 levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AßO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses.

Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons.

Background: Extracellular vesicles (EVs) carry bioactive molecules associated with various biological processes, including miRNAs. In both Huntington's disease (HD) models and human samples, altered expression of miRNAs involved in synapse regulation was reported. Recently, the use of EV cargo to reverse phenotypic alterations in disease models with synaptopathy as the end result of the pathophysiological cascade has become an interesting possibility. Methods: Here, we assessed the contribution of EVs to GABAergic synaptic alterations using a human HD model and studied the miRNA content of isolated EVs. Results: After differentiating human induced pluripotent stem cells into electrophysiologically active striatal-like GABAergic neurons, we found that HD-derived neurons displayed reduced density of inhibitory synapse markers and GABA receptor-mediated ionotropic signaling. Treatment with EVs secreted by control (CTR) fibroblasts reversed the deficits in GABAergic synaptic transmission and increased the density of inhibitory synapses in HD-derived neuron cultures, while EVs from HD-derived fibroblasts had the opposite effects on CTR-derived neurons. Moreover, analysis of miRNAs from purified EVs identified a set of differentially expressed miRNAs between manifest HD, premanifest, and CTR lines with predicted synaptic targets. Conclusion: The EV-mediated reversal of the abnormal GABAergic phenotype in HD-derived neurons reinforces the potential role of EV-miRNAs on synapse regulation.

Impacto de la pandemia por COVID-19 sobre un programa de consulta electrónica universal (e-consulta) entre médicos de Atención Primaria y cardiólogos / Impact of the COVID-19 pandemic above a universal electronic consultation program (e-consultation) between general practitioners and cardiologists

Introducción y objetivos Los programas de telemedicina entre clínico y paciente se han desarrollado con fuerza durante la pandemia de enfermedad por COVID-19, pero no hay datos de experiencias entre clínicos. Nuestro objetivo es analizar el impacto de la pandemia por COVID-19 en la actividad y resultados en salud de un programa de consulta electrónica universal (e-consulta) para todas las derivaciones de pacientes entre médicos de atención primaria y el Servicio de Cardiología de nuestra área. Métodos Analizamos mediante regresión logística a 25.121 pacientes con al menos una e-consulta entre 2018 y 2021 realizada con el Servicio de Cardiología de nuestra área sanitaria. También se realizó el análisis de regresión logística del impacto de la pandemia por COVID-19 sobre la resolución de la e-consulta y tiempo de espera de la atención, hospitalizaciones y mortalidad, tomando como referencia las consultas realizadas durante 2018. Resultados Observamos que una menor demora en la atención y resolución de la e-consulta (sin necesidad de atención presencial) se asociaba a un mejor pronóstico. Los períodos de pandemia COVID-19 presentaron similares resultados a los del 2018. Conclusiones Los resultados de nuestro estudio muestran una significativa reducción de las derivaciones a través de e-consulta durante el primer año de la pandemia por COVID-19 con recuperación posterior de la demanda asistencial sin que los períodos de pandemia se asociasen con peores resultados en salud. La reducción del tiempo de demora de resolución de la e-consulta y el grupo sin necesidad de consulta presencial se asociaron a un mejor pronóstico (AU)

Blackground and objective Virtual healthcare models, usually between healthcare professionals and patients, have developed strongly during the coronavirus disease 2019 (COVID-19) pandemic, but there are not data of models between clinicians. Our objective is to analyse the impact of the COVID-19 pandemic on the activity and health outcomes of the universal e-consultation program for patient referrals between primary care physicians and the Cardiology Department in our area. Methods Patients with at least one e-consultation between 2018 and 2021 were selected. We analysed the impact of the COVID-19 pandemic on activity and waiting time for care, hospitalizations and mortality, taking as a reference the consultations carried out during 2018. Results We analysed 25,121 patients. Through logistic regression analysis, it was observed that a shorter delay in care and resolution of the e-consultation without the need for face-to-face care were associated with a better prognosis. The COVID-19 pandemic periods (2019-2020 and 2020-2021) were not associated with worse health outcomes compared to 2018. Conclusions The results of our study show a significant reduction in e-consult referrals during the first year of the COVID-19 pandemic with a subsequent recovery in the demand for care without the pandemic periods being associated with worse outcomes. The reduction in the time elapsed for solving the e-consult and no need for in-person visit were associated with better outcomes (AU)

[Impact of the COVID-19 pandemic above a universal electronic consultation program (e-consultation) between general practitioners and cardiologists]. / Impacto de la pandemia por COVID-19 sobre un programa de consulta electrónica universal (e-consulta) entre médicos de Atención Primaria y cardiólogos.

Blackground and objective: Virtual healthcare models, usually between healthcare professionals and patients, have developed strongly during the coronavirus disease 2019 (COVID-19) pandemic, but there are not data of models between clinicians. Our objective is to analyse the impact of the COVID-19 pandemic on the activity and health outcomes of the universal e-consultation program for patient referrals between primary care physicians and the Cardiology Department in our area. Methods: Patients with at least one e-consultation between 2018 and 2021 were selected. We analysed the impact of the COVID-19 pandemic on activity and waiting time for care, hospitalizations and mortality, taking as a reference the consultations carried out during 2018. Results: We analysed 25,121 patients. Through logistic regression analysis, it was observed that a shorter delay in care and resolution of the e-consultation without the need for face-to-face care were associated with a better prognosis. The COVID-19 pandemic periods (2019-2020 and 2020-2021) were not associated with worse health outcomes compared to 2018. Conclusions: The results of our study show a significant reduction in e-consult referrals during the first year of the COVID-19 pandemic with a subsequent recovery in the demand for care without the pandemic periods being associated with worse outcomes. The reduction in the time elapsed for solving the e-consult and no need for in-person visit were associated with better outcomes.

Reduction of class I histone deacetylases ameliorates ER-mitochondria cross-talk in Alzheimer's disease.

Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER-mitochondria cross-talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl-H3 in AD human cortex, and increased HDAC2-3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aß1-42 oligomers (AßO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER-Ca2+ retention and mitochondrial Ca2+ accumulation, mitochondrial depolarization and impaired ER-mitochondria cross-talk, as observed in 3xTg-AD mouse hippocampal neurons and AßO-exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial-associated ER membranes (MAM) in cells exposed to AßO upon Tac treatment, along with reduction in ER-mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER-mitochondria Ca2+ transfer and mitochondrial Ca2+ retention, while knockdown of HDAC3 decreased ER-Ca2+ accumulation in AßO-treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM-related proteins, and reduced Aß levels. These data demonstrate that Tac normalizes Ca2+ signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac-mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER-mitochondria communication as a promising target for innovative therapeutics in AD.

Impact of the COVID-19 pandemic upon a universal electronic consultation program (e-consultation) between general practitioners and cardiologists.

BACKGROUND AND OBJECTIVE: Virtual healthcare models, usually between healthcare professionals and patients, have developed strongly during the coronavirus disease 2019 (COVID-19) pandemic, but there are no data corresponding to models between clinicians. An analysis was made of the impact of the COVID-19 pandemic upon the activity and health outcomes of the universal e-consultation program for patient referrals between primary care physicians and the Cardiology Department in our healthcare area. METHODS: Patients with at least one e-consultation between 2018 and 2021 were selected. We analyzed the impact of the COVID-19 pandemic upon activity and waiting time for care, hospitalizations and mortality, taking as reference the consultations carried out during 2018. RESULTS: A total of 25,121 patients were analyzed. Logistic regression analysis showed a shorter delay in care and resolution of the e-consultation without the need for face-to-face care to be associated to a better prognosis. The COVID-19 pandemic periods (2019-2020 and 2020-2021) were not associated to poorer health outcomes compared to 2018. CONCLUSIONS: The results of our study show a significant reduction in e-consultation referrals during the first year of the COVID-19 pandemic, with a subsequent recovery in the demand for care, and without the pandemic periods being associated to poorer outcomes. The reduction in time elapsed for resolving the e-consultations and no need for face-to-face visits were associated to improved outcomes.

Mitochondrial and Redox Changes in Periodontitis and Type 2 Diabetes Human Blood Mononuclear Cells.

Periodontitis (PDT) and type 2 diabetes (T2D) have demonstrated a bidirectional relationship and imbalanced oxidative stress linked to mitochondrial dysfunction. Therefore, we investigated mitochondrial and redox (de)regulation in peripheral blood mononuclear cells (PBMCs) in comorbid T2D-PDT, compared to PDT, T2D patients, and control individuals. PBMCs were analyzed for mitochondrial respiration, reactive oxygen species, antioxidant proteins, and expression of Nrf2-target genes. PDT and T2D-PDT patients exhibited altered periodontal clinical markers, while T2D and T2D-PDT patients displayed increased blood HbA1c. Decreased oxygen consumption and ATP production were observed in the PDT patient's PBMCs. PDT and T2D-PDT PBMCs also evidenced increased H2O2 levels and reduced catalase levels (also detected in T2D patients), whereas a compromised glutathione cycle was observed in T2D-PDT patients. PBMCs from both T2D or T2D-PDT patients showed increased Nrf2 protein levels, enhanced GCL activity and GCL-catalytic subunit protein levels, and maintained GCLc, GST, and HO-1 mRNA levels. In contrast, the expressions of Nrf2-target genes were significantly diminished in the PDT patient's PBMCs. Decreased SOD1 and GST mRNA levels were also observed in CD3+CD8+-lymphocytes derived from PDT and T2D-PDT patients. In conclusion, PBMCs from T2D-PDT patients showed major redox changes, while mononuclear cells from PDT patients showed mitochondrial deregulation and reduced expression of Nrf2-target genes.

Restored Fyn Levels in Huntington's Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity.

N-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington's disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models. Thus, in this study, we aimed to explore the impact of HD-mediated altered Fyn levels at post-synaptic density (PSD), and their role in distorted NMDARs function and localization, and intracellular neuroprotective pathways in YAC128 mouse primary striatal neurons. We show that reduced synaptic Fyn levels and activity in HD mouse striatal neurons is related to decreased phosphorylation of synaptic GluN2B-composed NMDARs; this occurs concomitantly with augmented extrasynaptic NMDARs activity and currents and reduced cAMP response element-binding protein (CREB) activation, along with induction of cell death pathways. Importantly, expression of a constitutive active form of SKF reestablishes NMDARs localization, phosphorylation, and function at PSD in YAC128 mouse neurons. Enhanced SKF levels and activity also promotes CREB activation and reduces caspase-3 activation in YAC128 mouse striatal neurons. This work supports, for the first time, a relevant role for Fyn protein in PSD modulation, controlling NMDARs synaptic function in HD, and favoring neuroprotective pathways and cell survival. In this respect, Fyn Tyr kinase constitutes an important potential HD therapeutic target directly acting at PSD.

Mitochondrial and redox modifications in early stages of Huntington's disease.

Deficits in mitochondrial function and redox deregulation have been attributed to Huntington's disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. In the present study, we analysed changes in mitochondrial function and production of reactive oxygen species (ROS) at early stages and with disease progression. Studies were performed in vivo in human brain by PET using [64Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD carriers. In vivo brain [64Cu]-ATSM PET in YAC128 transgenic mouse and striatal and cortical isolated mitochondria were assessed at presymptomatic (3 month-old, mo) and symptomatic (6-12 mo) stages. Pre-M HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number. Fibroblasts from Pre-M showed enhanced basal and maximal respiration, proton leak and increased hydrogen peroxide (H2O2) levels, later progressing in manifest HD. Mitochondria from fibroblasts of Pre-M HD carriers also showed reduced circularity, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. YAC128 mouse (at 3 months) striatal isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production, and increased complex II and III activities. YAC128 mouse striatal mitochondria also showed enhanced mitochondrial H2O2 levels and circularity, revealed by brain ultrastructure analysis, and defects in Ca2+ handling, supporting increased striatal susceptibility. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter progressing with manifest disease.

Mitochondrial function and dynamics in neural stem cells and neurogenesis: Implications for neurodegenerative diseases.

Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.

Cytotoxic and antiparasitic activities of diphosphine-metal complexes of group 10 containing acylthiourea as ligands.

In this work, group 10 transition metal complexes bearing dppe [1,2-bis(diphenylphosphino)ethane] and acylthiourea ligands were evaluated for their cytotoxic and antiparasitic activities. Six new complexes with a general formula [M(Ln)(dppe)]BF4 [where M = NiII, PdII or PtII; Ln = N, N'-dimethyl-N-benzoyl thiourea (L1) or N, N'-dimethyl-N-tiofenyl thiourea (L2) were synthesized and characterized by infrared, NMR (31P{1H}, 1H and 13C{1H}) spectroscopies, elemental analysis and molar conductivity. The structures of the complexes were confirmed by X-ray diffraction technique. The biological activity of the complexes was evaluated on breast cancer cells (MDA-MB-231 and MCF-7) and causative agents of chagas disease and leishmaniasis. The complexes presented higher cytotoxicity for breast cancer cell lines compared to non-tumor cells. Nickel complexes stood out when evaluated against the triple-negative breast cancer line (MDA-MB-231), presenting considerably lower IC50 values (about 10 to 22×), when compared to palladium and platinum complexes, and the cisplatin drug. When evaluated on the triple-negative line (MDA-MB-231), the complexes [Ni(L2)(dppe)]BF4(2), [Pd(L2)(dppe)]BF4(4) and [Pt(L2)(dppe)]BF4(6) were able to induce cell morphological changes, influence on the cell colony formation and the size of the cells. The complexes inhibit cell migration and cause changes to the cell cytoskeleton and nuclear arrangement. In the same cell line, the compounds caused cell arrest in the Sub-G1 phase of the cell cycle. The compounds were also tested against the Trypanosom Cruzi (T. cruzi) and Leishmania sp. parasites, which cause Chagas and leishmaniasis disease, respectively. The compounds showed good anti-parasitic activity, mainly for T. cruzi, with lower IC50 values, when compared to the commercial drug, benznidazole. The compounds interact with CT-DNA, indicating that interaction occurs by the minor groove of the biomolecule.

Salt stress and organic fertilization on the growth and biochemical metabolism of Hylocereus costaricensis (red pitaya) seedlings.

Red pitaya (Hylocereus costaricensis) is a promising species, with high cultivation potential due to the organoleptic and functional qualities of its fruits. However, irrigation water salinity can affect the crop yield. Therefore, materials rich in organic substances can minimize the damage caused by excess salts in soil and/or water. Thus, the objective of this study was to evaluate the influence of organic matter sources as attenuators of salt stress on the production and biochemical responses of red pitaya seedlings. A completely randomized design in 4 × 5 factorial scheme, with five sources of organic matter (humus, sheep manure, biofertilizer, organic compost and sand + soil) and four salinities (0.6, 2.6, 4.6 and 6.6 dS m-1) with four replicates and two plants per plot was used. The shoot length, root length, cladode diameter, number of cladodes, number of sprotus, root volume, shoot dry mass, root dry mass and total dry mass, root and shoot dry mass ratio, chlorophyll a, b and total, amino acids and soluble sugars were evaluated at 120 days after the treatments began to be applied. Red pitaya is moderately tolerant to salinity (ECw from 4.0 to 6.0 dS m-1). Organic compost and sheep manure attenuate the harmful effects of salinity on red pitaya seedlings. Under salt stress conditions, red pitaya plants increase their levels of proline, amino acids and total sugars.

Simultaneous Alteration of the Circadian Variation of Memory, Hippocampal Synaptic Plasticity, and Metabolism in a Triple Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive memory deficits accompanied by synaptic and metabolic deficits, namely of mitochondrial function. AD patients also display a disrupted circadian pattern. Thus, we now compared memory performance, synaptic plasticity, and mitochondria function in 24-week-old non-transgenic (non-Tg) and triple transgenic male mice modeling AD (3xTg-AD) at Zeitgeber 04 (ZT-4, inactive phase) and ZT-16 (active phase). Using the Morris water maze test to minimize the influence of circadian-associated locomotor activity, we observed a circadian variation in hippocampus-dependent learning performance in non-Tg mice, which was impaired in 3xTg-AD mice. 3xTg-AD mice also displayed a lack of circadian variation of their performance in the reversal spatial learning task. Additionally, the amplitude of hippocampal long-term potentiation also exhibited a circadian profile in non-Tg mice, which was not observed in 3xTg-AD mice. Moreover, cerebral cortical synaptosomes of non-Tg mice also displayed a circadian variation of FCCP-stimulated oxygen consumption as well as in mitochondrial calcium retention that were blunted in 3xTg-AD mice. In sum, this multidimensional study shows that the ability to maintain a circadian oscillation in brain behavior, synaptic plasticity, and synaptic mitochondria function are simultaneously impaired in 3xTg-AD mice, highlighting the effects of circadian misalignment in AD.

Mechanistic perspectives on differential mitochondrial-based neuroprotective effects of several carnitine forms in Alzheimer's disease in vitro model.

Mitochondrial deregulation has emerged as one of the earliest pathological events in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Improvement of mitochondrial function in AD has been considered a relevant therapeutic approach. L-carnitine (LC), an amino acid derivative involved in the transport of long-chain fatty acids into mitochondria, was previously demonstrated to improve mitochondrial function, having beneficial effects in neurological disorders; moreover, acetyl-L-carnitine (ALC) is currently under phase 4 clinical trial for AD (ClinicalTrials.gov NCT01320527). Thus, in the present study, we investigated the impact of different forms of carnitines, namely LC, ALC and propionyl-L-carnitine (PLC) on mitochondrial toxicity induced by amyloid-beta peptide 1-42 oligomers (AßO; 1 µM) in mature rat hippocampal neurons. Our results indicate that 5 mM LC, ALC and PLC totally rescued the mitochondrial membrane potential and alleviated both the decrease in oxygen consumption rates and the increase in mitochondrial fragmentation induced by AßO. These could contribute to the prevention of neuronal death by apoptosis. Moreover, only ALC ameliorated AßO-evoked changes in mitochondrial movement by reducing the number of stationary mitochondria and promoting reversal mitochondrial movement. Data suggest that carnitines (LC, ALC and PLC) may act differentially to counteract changes in mitochondrial function and movement in neurons subjected to AßO, thus counteracting AD-related pathological phenotypes.

Yellow grease in sheep diets: intake and digestibility / [Óleo residual de fritura em dietas para ovinos: consumo e digestibilidade]

This study aimed to assess the effects of yellow grease supplementation on the intake, digestibility, and nitrogen balance in sheep. Twenty Santa Inês lambs with a mean age of 95 ± 10 d and body weight of 19.29 ± 3.17kg were evaluated in a completely randomized design. The diets were supplemented with oil at concentrations of 0, 20, 40, 60, and 80 gkg-1 of dry matter (DM) of the concentrate. The diets were based on roughage and concentrate (50:50). The experimental period lasted 19 d and included 14 adaptation days and five collection days for the total supplied diet, orts, feces, and urine. Supplementation with yellow grease had no significant effect on the intake of DM, crude protein (CP), neutral detergent fiber (NDF), or non-fiber carbohydrates (NFC). However, the ether extract (EE) intake increased linearly with supplementation of yellow grease. Moreover, no effect was observed for DM, CP, NDF, and NFC digestibility and nitrogen balance. EE digestibility increased linearly with the yellow grease dietary supplementation. Thus, sheep dietary supplementation with yellow grease may be used at a level of up to 80 gkg-1 of DM of concentrate without impairing nutrient intake and digestibility.(AU)

Objetivou-se, com o estudo, avaliar os efeitos do óleo residual de fritura, em dietas para ovinos, sob o consumo, a digestibilidade e o balanço de nitrogênio. Foram utilizados 20 cordeiros Santa Inês, com idade de 95 ± 10 dias e peso corporal de 19,29 ± 3,17kg, em delineamento inteiramente ao acaso. As dietas continham óleo de fritura nas concentrações de 0; 20; 40; 60 e 80gkg-1 da matéria seca (MS) do concentrado. As dietas tinham relação volumoso:concentrado de 50:50. O período experimental foi de 19 dias, incluindo 14 dias em adaptação e cinco dias de coleta do fornecido, das sobras, das fezes e da urina. A suplementação com óleo de fritura não alterou o consumo de MS, proteína bruta (PB), matéria orgânica (MO), fibra em detergente neutro (FDN) e carboidratos não fibrosos (CNF). Entretanto, o consumo de extrato etéreo (EE) aumentou com a inclusão do óleo. Não foi observado efeito na digestibilidade da MS, da PB, da FDN, dos CNF e no balanço de nitrogênio. A digestibilidade do EE aumentou com a inclusão do óleo. Assim, a inclusão de óleo de fritura em dietas para ovinos pode ser utilizada em até 80gkg-1 da MS do concentrado, sem limitar ingestão e digestibilidade dos nutrientes.(AU)

The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models.

Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca2+ signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Pridopidine effects on mitochondrial dynamics were assessed in primary neurons from YAC128 HD mice expressing the mutant human HTT gene. We observe that pridopidine prevents the disruption of mitochondria-ER contact sites and improves the co-localization of inositol 1,4,5-trisphosphate receptor (IP3R) and its chaperone S1R with mitochondria in YAC128 neurons, leading to increased mitochondrial activity, elongation, and motility. Increased mitochondrial respiration is also observed in YAC128 neurons and in pridopidine-treated HD human neural stem cells (hNSCs). ROS levels were assessed after oxidative insult or S1R knockdown in pridopidine-treated YAC128 neurons, HD hNSCs, and human HD lymphoblasts. All HD models show increased ROS levels and deficient antioxidant response, which are efficiently rescued with pridopidine. Importantly, pridopidine treatment before H2O2-induced mitochondrial dysfunction and S1R presence are required for HD cytoprotection. YAC128 mice treated at early/pre-symptomatic age with pridopidine show significant improvement in motor coordination, indicating a delay in symptom onset. Additionally, in vivo pridopidine treatment reduces mitochondrial ROS levels by normalizing mitochondrial complex activity. In conclusion, S1R-mediated enhancement of mitochondrial function contributes to the neuroprotective effects of pridopidine, providing insight into its mechanism of action and therapeutic potential.

Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling.

BACKGROUND: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential. RESULTS: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein. CONCLUSION: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases.

Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aß) oligomers (AßO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AßO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AßO. Naturally-derived compounds have been proposed as potential modifiers of Aß-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AßO. We examined the protective effect of boldine (1-10 µM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AßO (24-48 h). We found that boldine interacts with Aß in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AßO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AßO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AßO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aß and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aß in vivo.