New Breakfast Cereal Developed with Sprouted Whole Ryegrass Flour: Evaluation of Technological and Nutritional Parameters.

Ryegrass is one such cereal that has been underutilized in human nutrition despite its high nutritional and functional value due to the presence of phytochemicals and dietary fibers. Exploiting ryegrass for human consumption is an exciting option, especially for countries that do not produce wheat, as it is easily adaptable and overgrows, making it economically viable. This study evaluated the nutritional content of γ-aminobutyric acid and bioactive compounds (total soluble phenolic compounds) and the physicochemical and technological properties of partially substituting maize flour (MF) with sprouted whole ryegrass flour (SR) in developing extrusion-cooked breakfast cereals. A completely randomized design with substitutions ranging from 0 to 20% of MF with SR was employed as the experimental strategy (p < 0.05). Partial incorporation of SR increased the content of γ-aminobutyric acid and total soluble phenolic compounds. Using sprouted grains can adversely affect the technological quality of extruded foods, mainly due to the activation of the amylolytic enzymes. Still, ryegrass, with its high dietary fiber and low lipid content, mitigates these negative effects. Consequently, breakfast cereals containing 4 and 8% SR exhibited better physicochemical properties when compared to SR12, SR16, SR20, and USR10, presenting reduced hardness and increased crispness, and were similar to SR0. These results are promising for ryegrass and suggest that combining the age-old sprouting process with extrusion can enhance the nutritional quality and bioactive compound content of cereal-based breakfast products while maintaining some technological parameters, especially crispiness, expansion index, water solubility index, and firmness, which are considered satisfactory.

Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart.

Long QT syndrome (LQTS) can lead to ventricular arrhythmia and sudden cardiac death. The most common congenital cause of LQTS is mutations in the channel subunits generating the cardiac potassium current IKs. Zebrafish (Danio rerio) have been proposed as a powerful system to model human cardiac diseases due to the similar electrical properties of the zebrafish heart and the human heart. We used high-resolution all-optical electrophysiology on ex vivo zebrafish hearts to assess the effects of IKs analogues on the cardiac action potential. We found that chromanol 293B (an IKs inhibitor) prolonged the action potential duration (APD) in the presence of E4031 (an IKr inhibitor applied to drug-induced LQT2), and to a lesser extent, in the absence of E4031. Moreover, we showed that PUFA analogues slightly shortened the APD of the zebrafish heart. However, PUFA analogues failed to reverse the APD prolongation in drug-induced LQT2. However, a more potent IKs activator, ML-277, partially reversed the APD prolongation in drug-induced LQT2 zebrafish hearts. Our results suggest that IKs plays a limited role in ventricular repolarizations in the zebrafish heart under resting conditions, although it plays a more important role when the IKr is compromised, as if the IKs in zebrafish serves as a repolarization reserve as in human hearts. This study shows that potent IKs activators can restore the action potential duration in drug-induced LQT2 in the zebrafish heart.

Pairing a user-friendly machine-learning animal sound detector with passive acoustic surveys for occupancy modeling of an endangered primate.

Population declines and range contractions due to habitat loss are pervasive among nonhuman primates, with 60% of species threatened with extinction. However, the extensive vocal activity displayed by many primates makes them excellent candidates for passive acoustic surveys. Passive acoustic survey data is increasingly being used to support occupancy models, which have proven to be an efficient means of estimating both population trends and distributions. Passive acoustic surveys can be conducted relatively quickly and at broad scales, but efficient audio data processing has long proven elusive. The machine learning algorithm BirdNET was originally developed for birds but was recently expanded to include nonavian taxa. We demonstrate that BirdNET can accurately and efficiently identify an endangered primate, the Yucatán black howler monkey (Alouatta pigra), by sound in passive acoustic survey data (collected in southeastern Chiapas, Mexico), enabling us to use a single-season occupancy model to inform further survey efforts. Importantly, we also generated data on up to 286 co-occurring bird species, demonstrating the value of integrated animal sound classification tools for biodiversity surveys. BirdNET is freely available, requires no computer science expertise to use, and can readily be expanded to include more species (e.g., its species list recently tripled to >3000), suggesting that passive acoustic surveys, and thus occupancy modeling, for primate conservation could rapidly become much more accessible. Importantly, the long history of bioacoustics in primate research has yielded a wealth of information about their vocal behavior, which can facilitate appropriate survey design and data interpretation.

Performance of Thermoplastic Extrusion, Germination, Fermentation, and Hydrolysis Techniques on Phenolic Compounds in Cereals and Pseudocereals.

Bioactive compounds, such as phenolic compounds, are phytochemicals found in significant amounts in cereals and pseudocereals and are usually evaluated by spectrophotometric (UV-VIS), HPLC, and LC-MS techniques. However, their bioavailability in grains is quite limited. This restriction on bioavailability and bioaccessibility occurs because they are in conjugated polymeric forms. Additionally, they can be linked through chemical esterification and etherification to macro components. Techniques such as thermoplastic extrusion, germination, fermentation, and hydrolysis have been widely studied to release phenolic compounds in favor of their bioavailability and bioaccessibility, minimizing the loss of these thermosensitive components during processing. The increased availability of phenolic compounds increases the antioxidant capacity and favor their documented health promoting.

Andean Sprouted Pseudocereals to Produce Healthier Extrudates: Impact in Nutritional and Physicochemical Properties.

The tailored formulation of raw materials and the combination of grain germination and extrusion processes could be a promising strategy to achieve the desired goal of developing healthier expanded extrudates without compromising sensory properties. In this study, modifications in the nutritional, bioactive profile and physicochemical properties of corn extrudates as influenced by the complete or partial replacement by sprouted quinoa (Chenopodium quinoa Willd) and cañihua (Chenopodium pallidicaule Aellen) were investigated. A simplex centroid mixture design was used to study the effects of formulation on nutritional and physicochemical properties of extrudates, and a desirability function was applied to identify the optimal ingredient ratio in flour blends to achieve desired nutritional, texture and color goals. Partial incorporation of sprouted quinoa flour (SQF) and cañihua flour (SCF) in corn grits (CG)-based extrudates increased phytic acid (PA), total soluble phenolic compounds (TSPC), γ-aminobutyric acid (GABA) and oxygen radical antioxidant activity (ORAC) of the extrudates. Sprouted grain flour usually results in an deleterious effect physicochemical properties of extrudates, but the partial mixture of CG with SQF and SCF circumvented the negative effect of germinated flours, improving technological properties, favoring the expansion index and bulk density and increasing water solubility. Two optimal formulations were identified: 0% CG, 14% SQF and 86% SCF (OPM1) and 24% CG, 17% SQF and 59% SCF (OPM2). The optimized extrudates showed a reduced amount of starch and remarkably higher content of total dietary fiber, protein, lipids, ash, PA, TSPC, GABA and ORAC as compared to those in 100% CG extrudates. During digestion, PA, TSPC, GABA and ORAC showed good stability in physiological conditions. Higher antioxidant activity and amounts of bioaccessible TSPC and GABA were found in OPM1 and OPM2 digestates as compared to those in 100% CG extrudates.

Social Justice is the Spirit and Aim of an Applied Science of Human Behavior: Moving from Colonial to Participatory Research Practices.

It is time for a paradigm shift in the science of applied behavior analysis. Our current approach to applied research perpetuates power imbalances. We posit that the purpose of applied behavior analysis is to enable and expand human rights and to eliminate the legacies of colonial, oppressive social structures. We report the findings from our examination of the content of our flagship applied research journal. We reviewed 50 years of applied experiments from the standpoint of respect, beneficence, justice, and the participation of individuals and communities. Although there is some promise and movement toward inclusion, our findings indicate that we have not prioritized full participation across all segments of society, especially persons and communities that are marginalized. Social justice rests on the belief that human life is to be universally cherished and valued. In this article, we suggest that policies, strategies, and research practices within our field be interwoven with a commitment to social justice, including racial justice, for all. We offer recommendations to neutralize and diffuse power imbalances and to work toward a shift from colonial to participatory practices in the methods and aims of our applied science.

Identification of a critical binding site for local anaesthetics in the side pockets of Kv 1 channels.

BACKGROUND AND PURPOSE: Local anaesthetics block sodium and a variety of potassium channels. Although previous studies identified a residue in the pore signature sequence together with three residues in the S6 segment as a putative binding site, the precise molecular basis of inhibition of Kv channels by local anaesthetics remained unknown. Crystal structures of Kv channels predict that some of these residues point away from the central cavity and face into a drug binding site called side pockets. Thus, the question arises whether the binding site of local anaesthetics is exclusively located in the central cavity or also involves the side pockets. EXPERIMENTAL APPROACH: A systematic functional alanine mutagenesis approach, scanning 58 mutants, together with in silico docking experiments and molecular dynamics simulations was utilized to elucidate the binding site of bupivacaine and ropivacaine. KEY RESULTS: Inhibition of Kv 1.5 channels by local anaesthetics requires binding to the central cavity and the side pockets, and the latter requires interactions with residues of the S5 and the back of the S6 segments. Mutations in the side pockets remove stereoselectivity of inhibition of Kv 1.5 channels by bupivacaine. Although binding to the side pockets is conserved for different local anaesthetics, the binding mode in the central cavity and the side pockets shows considerable variations. CONCLUSION AND IMPLICATIONS: Local anaesthetics bind to the central cavity and the side pockets, which provide a crucial key to the molecular understanding of their Kv channel affinity and stereoselectivity, as well as their spectrum of side effects.

KV1.5-KVß1.3 Recycling Is PKC-Dependent.

KV1.5 channel function is modified by different regulatory subunits. KVß1.3 subunits assemble with KV1.5 channels and induce a fast and incomplete inactivation. Inhibition of PKC abolishes the KVß1.3-induced fast inactivation, decreases the amplitude of the current KV1.5-KVß1.3 and modifies their pharmacology likely due to changes in the traffic of KV1.5-KVß1.3 channels in a PKC-dependent manner. In order to analyze this hypothesis, HEK293 cells were transfected with KV1.5-KVß1.3 channels, and currents were recorded by whole-cell configuration of the patch-clamp technique. The presence of KV1.5 in the membrane was analyzed by biotinylation techniques, live cell imaging and confocal microscopy approaches. PKC inhibition resulted in a decrease of 33 ± 7% of channels in the cell surface due to reduced recycling to the plasma membrane, as was confirmed by confocal microscopy. Live cell imaging indicated that PKC inhibition almost abolished the recycling of the KV1.5-KVß1.3 channels, generating an accumulation of channels into the cytoplasm. All these results suggest that the trafficking regulation of KV1.5-KVß1.3 channels is dependent on phosphorylation by PKC and, therefore, they could represent a clinically relevant issue, mainly in those diseases that exhibit modifications in PKC activity.

The unconventional biogenesis of Kv7.1-KCNE1 complexes.

The potassium channel Kv7.1 associates with the KCNE1 regulatory subunit to trigger cardiac I Ks currents. Although the Kv7.1/KCNE1 complex has received much attention, the subcellular compartment hosting the assembly is the subject of ongoing debate. Evidence suggests that the complex forms either earlier in the endoplasmic reticulum or directly at the plasma membrane. Kv7.1 and KCNE1 mutations, responsible for long QT syndromes, impair association and traffic, thereby altering I Ks currents. We found that Kv7.1 and KCNE1 do not assemble in the first stages of their biogenesis. Data support an unconventional secretory pathway for Kv7.1-KCNE1 that bypasses Golgi. This route targets channels to endoplasmic reticulum-plasma membrane junctions, where Kv7.1-KCNE1 assemble. This mechanism helps to resolve the ongoing controversy about the subcellular compartment hosting the association. Our results also provide new insights into I Ks channel localization at endoplasmic reticulum-plasma membrane junctions, highlighting an alternative anterograde trafficking mechanism for oligomeric ion channels.

Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms.

The cardiac ventricular action potential depends on several voltage-gated ion channels, including NaV, CaV, and KV channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (NaV, CaV, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

Protein supplement use and prevalence of microalbuminuria in gym members.

BACKGROUND: Protein supplement use is common in bodybuilders because protein supplements are thought to increase muscle mass by preventing protein catabolism during exercise routines. Information on the consequences of protein supplement use is scarce and contradictory. Therefore, the identification of a kidney damage marker, such as microalbuminuria, could be transcendent in preventing probable organ compromise in healthy persons. The aim of this study is to determine the presence of microalbuminuria in gym members and whether there is an associated risk with protein supplement use. METHODS: An analytic, descriptive, cross-sectional study was conducted. It included gym members whose clinical and nutritional histories were taken, identifying protein supplement use. Microalbuminuria was then determined through a random urine sample. Descriptive and inferential statistics were used for the data analysis. The objective was to determine the presence of microalbuminuria in gym members and whether there is an associated risk with protein supplement use. RESULTS: A total of 107 gym members, 71 men and 36 women, that met the inclusion criteria of the study were analyzed. Their mean age was 35±13 years, and the prevalence of microalbuminuria was 9.34%. There was active protein supplement use in 58% of the study participants, with a mean consumption duration of 16±22 months. No association with the presence of microalbuminuria was found (P=0.35). CONCLUSIONS: The prevalence of microalbuminuria in gym members was higher than that of the general healthy population and was not associated with protein supplement use.

Activation of Kv 7 channels as a novel mechanism for NO/cGMP-induced pulmonary vasodilation.

BACKGROUND AND PURPOSE: The NO/cGMP pathway represents a major physiological signalling controlling tone in pulmonary arteries (PA), and drugs activating this pathway are used to treat pulmonary arterial hypertension. Kv channels expressed in PA smooth muscle cells (PASMCs) are key determinants of vascular tone. We aimed to analyse the contribution of Kv 1.5 and Kv 7 channels in the electrophysiological and vasodilating effects evoked by NO donors and the GC stimulator riociguat in PA. EXPERIMENTAL APPROACH: Kv currents were recorded in isolated rat PASMCs using the patch-clamp technique. Vascular reactivity was assessed in a wire myograph. KEY RESULTS: The NO donors diethylamine NONOate diethylammonium (DEA-NO) and sodium nitroprusside hyperpolarized the membrane potential and induced a bimodal effect on Kv currents (augmenting the current between -40 and -10 mV and decreasing it at more depolarized potentials). The hyperpolarization and the enhancement of the current were suppressed by Kv 7 channel inhibitors and by the GC inhibitor ODQ but preserved when Kv 1.5 channels were inhibited. Additionally, DEA-NO enhanced Kv 7.5 currents in COS7 cells expressing the KCNQ5 gene. Riociguat increased Kv currents at all potentials ≥-40 mV and induced membrane hyperpolarization. Both effects were prevented by Kv 7 inhibition. Likewise, PA relaxation induced by NO donors and riociguat was attenuated by Kv 7 inhibitors. CONCLUSIONS AND IMPLICATIONS: NO donors and riociguat enhance Kv 7 currents, leading to PASMC hyperpolarization. This mechanism contributes to NO/cGMP-induced PA vasodilation. Our study identifies Kv 7 channels as a novel mechanism of action of vasodilator drugs used in the treatment of pulmonary arterial hypertension.

Utilidad de la monitorización ambulatoria de la presión arterial en mujeres con diabetes mellitus gestacional / Usefulness of blood pressure monitoring in patients with gestational diabetes mellitus

Antecedentes y objetivos: Las pacientes con diabetes mellitus gestacional (DMG) presentan un mayor riesgo de desarrollar hipertensión arterial inducida por el embarazo (HIE). La monitorización ambulatoria de presión arterial (MAPA) ha sido usada para detectar HIE y preeclampsia, pero hasta la fecha no ha sido suficientemente estudiada en DMG. El objetivo del presente trabajo es identificar de forma precoz, en mujeres con DMG, perfiles de presión arterial (PA), detectados mediante MAPA, que pudieran definir una población de mayor riesgo de desarrollar HIE y preeclampsia. Material y métodos: Estudio prospectivo en 93 pacientes con PA normal con DMG. Se les implantó entre la semana 28-32 de gestación la MAPA durante 24h (Spacelabs 90207) y se analizaron variables clínicas, analíticas y resultados obstétricos y perinatales. Resultados: La edad media fue 34,8±4,39años. Cinco pacientes (5,4%) desarrollaron HIE. Encontramos niveles más elevados de HbA1c (p=0,005) y microalbuminuria (p=0,001) entre las que desarrollaron HIE. Las pacientes con patrón no dipper (50,5%) presentaron cifras de PAS nocturna (106,7 vs 98,4mmHg) y PAD nocturna (64,8 vs 57,2mmHg) más elevadas (p<0,001). Se observó menor peso al nacimiento (3.084,57 vs 3.323,7; p=0,021) y menor semana de gestación en el momento del parto (38,67 vs 39,27 semanas; p=0,04) en pacientes con patrón no dipper respecto al dipper. La PAS nocturna elevada se asoció con un incremento significativo de la probabilidad de HIE (OR: 1,18; IC95%: 1,00-1,39; p=0,043). Conclusiones: En la DMG existen alteraciones tensionales con un predominio de patrón no dipper de PA y con valores más elevados de PAS y PAD nocturnos, pudiendo ser estas alteraciones predictoras de HIE. Los valores elevados de PAS nocturna aumentan el riesgo de desarrollo de HIE. Se requieren futuros estudios para determinar la relación entre las alteraciones tensionales y las complicaciones maternas y perinatales

Background and objective: Gestational diabetes mellitus (GDM) is associated to an increased risk of pregnancy-induced hypertension (PIH). Ambulatory blood pressure monitoring (ABPM) has been used to detect PIH and preeclampsia, but few data are currently available on its use in women with GDM. The aim of this study was to achieve early identification in women with GDM of BP profiles (detected by ABPM) that could define a population at greater risk of developing PIH and preeclampsia. Material and methods: A prospective study of 93 normotensive women with GDM in whom 24-h ABPM was performed (using a Spacelabs 90207 monitor) at 28-32 weeks of pregnancy. Clinical and laboratory variable and obstetric and perinatal outcomes were analyzed. Results: Mean age was 34.8±4.39years, and 5.4% of patients developed PIH. Higher levels of HbA1c (P=.005) and microalbumin (P=.001) were seen in patients with PIH. Patients with non-dipper patterns (50.5%) had higher values of night-time systolic BP (106.7 vs 98.4mmHg) and night-time diastolic BP (64.8 vs 57.2mmHg) (P<.001). Lower birth weights (3,084.57 vs 3,323.7) (P=.021) and shorter gestational age at delivery (38.67 vs 39.27 weeks) (P=.04) were found in women with non-dipper pattern. High night-time systolic BP significantly increased the chance of developing PIH (OR: 1.18; 95%CI: 1.00-1.39; P=.043). Conclusions: Patients with GDM have BP changes, with predominance of the non-dipper pattern and higher night-time systolic and diastolic BP, changes that could be useful predictors of PIH. High night-time systolic BP values increase the risk of developing PIH. Further studies are needed to ascertain the relationships between BP changes and obstetric and perinatal complications

Usefulness of blood pressure monitoring in patients with gestational diabetes mellitus. / Utilidad de la monitorización ambulatoria de la presión arterial en mujeres con diabetes mellitus gestacional.

BACKGROUND AND OBJECTIVE: Gestational diabetes mellitus (GDM) is associated to an increased risk of pregnancy-induced hypertension (PIH). Ambulatory blood pressure monitoring (ABPM) has been used to detect PIH and preeclampsia, but few data are currently available on its use in women with GDM. The aim of this study was to achieve early identification in women with GDM of BP profiles (detected by ABPM) that could define a population at greater risk of developing PIH and preeclampsia. MATERIAL AND METHODS: A prospective study of 93 normotensive women with GDM in whom 24-h ABPM was performed (using a Spacelabs 90207 monitor) at 28-32 weeks of pregnancy. Clinical and laboratory variable and obstetric and perinatal outcomes were analyzed. RESULTS: Mean age was 34.8±4.39years, and 5.4% of patients developed PIH. Higher levels of HbA1c (P=.005) and microalbumin (P=.001) were seen in patients with PIH. Patients with non-dipper patterns (50.5%) had higher values of night-time systolic BP (106.7 vs 98.4mmHg) and night-time diastolic BP (64.8 vs 57.2mmHg) (P<.001). Lower birth weights (3,084.57 vs 3,323.7) (P=.021) and shorter gestational age at delivery (38.67 vs 39.27 weeks) (P=.04) were found in women with non-dipper pattern. High night-time systolic BP significantly increased the chance of developing PIH (OR: 1.18; 95%CI: 1.00-1.39; P=.043). CONCLUSIONS: Patients with GDM have BP changes, with predominance of the non-dipper pattern and higher night-time systolic and diastolic BP, changes that could be useful predictors of PIH. High night-time systolic BP values increase the risk of developing PIH. Further studies are needed to ascertain the relationships between BP changes and obstetric and perinatal complications.

D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence.

KV7.1 and KCNE1 co-assemble to give rise to the IKs current, one of the most important repolarizing currents of the cardiac action potential. Its relevance is underscored by the identification of >500 mutations in KV7.1 and, at least, 36 in KCNE1, that cause Long QT Syndrome (LQTS). The aim of this study was to characterize the biophysical and cellular consequences of the D242N KV7.1 mutation associated with the LQTS. The mutation is located in the S4 transmembrane segment, within the voltage sensor of the KV7.1 channel, disrupting the conserved charge balance of this region. Perforated patch-clamp experiments show that, unexpectedly, the mutation did not disrupt the voltage-dependent activation but it removed the inactivation and slowed the activation kinetics of D242N KV7.1 channels. Biotinylation of cell-surface protein and co-immunoprecipitation experiments revealed that neither plasma membrane targeting nor co-assembly between KV7.1 and KCNE1 was altered by the mutation. However, the association of D242N KV7.1 with KCNE1 strongly shifted the voltage dependence of activation to more depolarized potentials (+50mV), hindering IKs current at physiologically relevant membrane potentials. Both functional and computational analysis suggest that the clinical phenotype of the LQTS patients carrying the D242N mutation is due to impaired action potential adaptation to exercise and, in particular, to increase in heart rate. Moreover, our data identify D242 aminoacidic position as a potential residue involved in the KCNE1-mediated regulation of the voltage dependence of activation of the KV7.1 channel.

Fludarabine Inhibits KV1.3 Currents in Human B Lymphocytes.

Fludarabine (F-ara-A) is a purine analog commonly used in the treatment of indolent B cell malignancies that interferes with different aspects of DNA and RNA synthesis. KV1.3 K+ channels are membrane proteins involved in the maintenance of K+ homeostasis and the resting potential of the cell, thus controlling signaling events, proliferation and apoptosis in lymphocytes. Here we show that F-ara-A inhibits KV currents in human B lymphocytes. Our data indicate that KV1.3 is expressed in both BL2 and Dana B cell lines, although total KV1.3 levels were higher in BL2 than in Dana cells. However, KV currents in the plasma membrane were similar in both cell lines and were abrogated by the specific KV1.3 channel inhibitor PAP-1, indicating that KV1.3 accounts for most of the KV currents in these cell lines. F-ara-A, at a concentration (3.5 µM) similar to that achieved in the plasma of fludarabine phosphate-treated patients (3 µM), inhibited KV1.3 currents by 61 ± 6.3% and 52.3 ± 6.3% in BL2 and Dana B cells, respectively. The inhibitory effect of F-ara-A was concentration-dependent and showed an IC50 value of 0.36 ± 0.04 µM and a nH value of 1.07 ± 0.15 in BL2 cells and 0.34 ± 0.13 µM (IC50 ) and 0.77 ± 0.11 (nH ) in Dana cells. F-ara-A inhibition of plasma membrane KV1.3 was observed irrespective of its cytotoxic effect on the cells, BL2 cells being sensitive and Dana cells resistant to F-ara-A cytotoxicity. Interestingly, PAP-1, at concentrations as high as 10 µM, did not affect the viability of BL2 and Dana cells, indicating that blockage of KV1.3 in these cells is not toxic. Finally, F-ara-A had no effect on ectopically expressed KV1.3 channels, suggesting an indirect mechanism of current inhibition. In summary, our results describe the inhibitory effect of F-ara-A on the activity of KV1.3 channel. Although KV1.3 inhibition is not sufficient to induce cell death, further research is needed to determine whether it might still contribute to F-ara-A cytotoxicity in sensitive cells or be accountable for some of the clinical side effects of the drug.

In-Depth Study of the Interaction, Sensitivity, and Gating Modulation by PUFAs on K+ Channels; Interaction and New Targets.

Voltage gated potassium channels (KV) are membrane proteins that allow selective flow of K+ ions in a voltage-dependent manner. These channels play an important role in several excitable cells as neurons, cardiomyocytes, and vascular smooth muscle. Over the last 20 years, it has been shown that omega-3 polyunsaturated fatty acids (PUFAs) enhance or decrease the activity of several cardiac KV channels. PUFAs-dependent modulation of potassium ion channels has been reported to be cardioprotective. However, the precise cellular mechanism underlying the cardiovascular benefits remained unclear in part because new PUFAs targets and signaling pathways continue being discovered. In this review, we will focus on recent data available concerning the following aspects of the KV channel modulation by PUFAs: (i) the exact residues involved in PUFAs-KV channels interaction; (ii) the structural PUFAs determinants important for their effects on KV channels; (iii) the mechanism of the gating modulation of KV channels and, finally, (iv) the PUFAs modulation of a few new targets present in smooth muscle cells (SMC), KCa1.1, K2P, and KATP channels, involved in vascular relaxation.

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease.

Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD.