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Bocconia arborea S. Watson (Papaveraceae) is an abundant medicinal plant in the North of Morelos State, Mexico, which is used for the treatment of several diseases. The aim of current investigation was to isolate the compounds responsible of the relaxant effect shown by the active extracts. Thus, phytochemical bio-guided fractionation allowed the isolation of angoline (1), dihydrosanguinarine (2), bocconarborine A (3), oxisanguinarine (4), and oxychelerithrine (5) from dichloromethanic and methanolic extracts from the bark of Bocconia arborea (Papaveraceae). The relaxant study on aortic and tracheal rat rings of all benzophenanthridines indicates that 1 was the most active compound of the entire series investigated. Angoline (1) induces its relaxant effect by a concentration-dependent manner through the calcium channel blockade in both tissues.

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Calcium is a secondary messenger that interacts with several cellular proteins, regulates various physiological processes, and plays a role in diseases such as viral infections. Next-generation probiotics and live biotherapeutic products are linked to the regulation of intracellular calcium levels. Some viruses can manipulate calcium channels, pumps, and membrane receptors to alter calcium influx and promote virion production and release. In this study, we examined the use of bacteria for the prevention and treatment of viral diseases, such as coronavirus of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination programs have helped reduce disease severity; however, there is still a lack of well-recognized drug regimens for the clinical management of COVID-19. SARS-CoV-2 interacts with the host cell calcium (Ca2+), manipulates proteins, and disrupts Ca2+ homeostasis. This article explores how viruses exploit, create, or exacerbate calcium imbalances, and the potential role of probiotics in mitigating viral infections by modulating calcium signaling. Pharmacological strategies have been developed to prevent viral replication and block the calcium channels that serve as viral receptors. Alternatively, probiotics may interact with cellular calcium influx, such as Lactobacillus spp. The interaction between Akkermansia muciniphila and cellular calcium homeostasis is evident. A scientific basis for using probiotics to manipulate calcium channel activity needs to be established for the treatment and prevention of viral diseases while maintaining calcium homeostasis. In this review article, we discuss how intracellular calcium signaling can affect viral replication and explore the potential therapeutic benefits of probiotics.

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Autophagic flux plays a crucial role in various diseases. Recently, the lysosomal ion channel TRPML1 has emerged as a promising target in lysosomal storage diseases, such as mucolipidosis. The discovery of mucolipin synthetic agonist-1 (ML-SA1) has expanded our understanding of TRPML1's function and its potential therapeutic uses. However, ML-SA1 is a racemate with limited cellular potency and poor water solubility. In this study, we synthetized rac-ML-SA1, separated the enantiomers by chiral liquid chromatography and determined their absolute configuration by vibrational circular dichroism (VCD). In addition, we focused on investigating the impact of each enantiomer of ML-SA1 on the TRPML1-TFEB axis. Our findings revealed that (S)-ML-SA1 acts as an agonist for TRPML1 at the lysosomal membrane. This activation prompts transcription factor EB (TFEB) to translocate from the cytosol to the nucleus in a dose-dependent manner within live cells. Consequently, this signaling pathway enhances the expression of coordinated lysosomal expression and regulation (CLEAR) genes and activates autophagic flux. Our study presents evidence for the potential use of (S)-ML-SA1 in the development of new therapies for lysosomal storage diseases that target TRPML1.

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Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Cav1.2 and Cav1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 µg/µL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 µg/µL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 µg/µL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Cav1.2 and Cav1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction.

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In skeletal muscle (SM), inward Ca2+-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca2+-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca2+-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca2+-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca2+-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca2+-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca2+-uptake. 5) The denaturation profile of the SERCA Ca2+-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca2+-binding domain, affecting SR Ca2+-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.

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Introduction: Recent studies suggest that calcium channel blockers (CCBs) could reduce the risk of active tuberculosis and improve clinical outcomes. We aimed to synthesize the evidence regarding the effect of CCBs on the risk of developing active tuberculosis and mortality. Methods: We systematically searched for observational studies and clinical trials published in six databases until 31 August 2023, following a PECO/PICO strategy. Results: We included eight observational studies, 4,020,830 patients, among whom 241,761 had diabetes mellitus and 30,397 had active tuberculosis. According to our results, CCBs reduce the risk of developing active tuberculosis by 29% (RR 0.71; 95% CI 0.67-0.75) in patients with and without diabetes mellitus. However, CCBs do not show any benefit in terms of tuberculosis-related mortality (RR 1.00; 95% CI 0.98-1.02). For both outcomes, no statistical heterogeneity was found (I2 = 0, p > 0.10). This protective effect of CCBs on the risk of active tuberculosis remained independent of the type of patient (with diabetes mellitus vs. general population) or the class of CCB administered (DHP-CCB vs. non-DHP-CCB) (test for subgroup differences I2 = 0, p > 0.10). However, this beneficial effect was more significant among the general population (RR 0.70; 95% CI 0.66-0.74) compared to patients with diabetes mellitus (RR 0.72; 95% CI 0.61-0.86) and among those patients treated with DHP-CCBs (RR 0.69; 95% CI 0.63-0.74) compared to patients treated with non-DHP-CCBs (RR 0.72; 95% CI 0.67-0.78). Conclusion: CCBs may reduce the risk of active TB in patients with diabetes and the general population. On the contrary, CCBs do not seem to have a protective effect on tuberculosis-related mortality. However, more evidence is still needed. We recommend developing clinical trials to verify these findings, including more diverse populations. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=352129].

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BACKGROUND: Voltage-gated calcium channels (VGCCs) play an important role in pain development and maintenance. As Cav2.2 and Cav3.2 channels have been identified as potential drug targets for analgesics, the participation of Cav2.3 (that gives rise to R-type calcium currents) in pain and analgesia remains incompletely understood. OBJECTIVE: Identify the participation of Cav2.3 in pain and analgesia. METHODS: To map research in this area as well as to identify any existing gaps in knowledge on the potential role of Cav2.3 in pain signalling, we conducted this scoping review. We searched PubMed and SCOPUS databases, and 40 articles were included in this study. Besides, we organized the studies into 5 types of categories within the broader context of the role of Cav2.3 in pain and analgesia. RESULTS: Some studies revealed the expression of Cav2.3 in pain pathways, especially in nociceptive neurons at the sensory ganglia. Other studies demonstrated that Cav2.3-mediated currents could be in-hibited by analgesic/antinociceptive drugs either indirectly or directly. Some articles indicated that Cav2.3 modulates nociceptive transmission, especially at the pre-synaptic level at spinal sites. There are studies using different rodent pain models and approaches to reduce Cav2.3 activity or expression and mostly demonstrated a pro-nociceptive role of Cav2.3, despite some contradictory findings and deficiencies in the description of study design quality. There are three studies that reported the association of single-nucleotide polymorphisms in the Cav2.3 gene (CACNA1E) with postoperative pain and opioid consumption as well as with the prevalence of migraine in patients. CONCLUSION: Cav2.3 is a target for some analgesic drugs and has a pro-nociceptive role in pain.

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Asthma is a condition in which a person's airways become inflamed, narrowed, and produce greater amounts of mucus than normal. It can cause shortness of breath, chest pain, coughing, or wheezing. In some cases, symptoms may be exacerbated. Thus, the current study was designed to determine the mechanism of action of 6-aminoflavone (6-NH2F) in ex vivo experiments, as well as to determine its toxicity in acute and sub-chronic murine models. Tissues were pre-incubated with 6-NH2F, and concentration-response curves to carbachol-induced contraction were constructed. Therefore, tracheal rings pre-treated with glibenclamide, 2-aminopyridine, or isoproterenol were contracted with carbachol (1 µM), then 6-NH2F relaxation curves were obtained. In other sets of experiments, to explore the calcium channel role in the 6-NH2F relaxant action, tissues were contracted with KCl (80 mM), and 6-NH2F was cumulatively added to induce relaxation. On the other hand, tissues were pre-incubated with the test sample, and after that, CaCl2 concentration-response curves were developed. In this context, 6-NH2F induced significant relaxation in ex vivo assays, and the effect showed a non-competitive antagonism pattern. In addition, 6-NH2F significantly relaxed the contraction induced by KCl and CaCl2, suggesting a potential calcium channel blockade, which was corroborated by in silico molecular docking that was used to approximate the mode of interaction with the L-type Ca2+ channel, where 6-NH2F showed lower affinity energy when compared with nifedipine. Finally, toxicological studies revealed that 6-NH2F possesses pharmacological safety, since it did not produce any toxic effect in both acute and sub-acute murine models. In conclusion, 6-aminoflavone exerted significant relaxation through calcium channel blockade, and the compound seems to be safe.

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The Buthidae family of scorpions consists of arthropods with significant medical relevance, as their venom contains a diverse range of biomolecules, including neurotoxins that selectively target ion channels in cell membranes. These ion channels play a crucial role in regulating physiological processes, and any disturbance in their activity can result in channelopathies, which can lead to various diseases such as autoimmune, cardiovascular, immunological, neurological, and neoplastic conditions. Given the importance of ion channels, scorpion peptides represent a valuable resource for developing drugs with targeted specificity for these channels. This review provides a comprehensive overview of the structure and classification of ion channels, the action of scorpion toxins on these channels, and potential avenues for future research. Overall, this review highlights the significance of scorpion venom as a promising source for discovering novel drugs with therapeutic potential for treating channelopathies.

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Venoms from tarantulas contain low molecular weight vasodilatory compounds whose biological action is conceived as part of the envenomation strategy due to its propagative effects. However, some properties of venom-induced vasodilation do not match those described by such compounds, suggesting that other toxins may cooperate with these ones to produce the observed biological effect. Owing to the distribution and function of voltage-gated ion channels in blood vessels, disulfide-rich peptides isolated from venoms of tarantulas could be conceived into potential vasodilatory compounds. However, only two peptides isolated from spider venoms have been investigated so far. This study describes for the first time a subfraction containing inhibitor cystine knot peptides, PrFr-I, obtained from the venom of the tarantula Poecilotheria regalis. This subfraction induced sustained vasodilation in rat aortic rings independent of vascular endothelium and endothelial ion channels. Furthermore, PrFr-I decreased calcium-induced contraction of rat aortic segments and reduced extracellular calcium influx to chromaffin cells by the blockade of L-type voltage-gated calcium channels. This mechanism was unrelated to the activation of potassium channels from vascular smooth muscle, since vasodilation was not affected in the presence of TEA, and PrFr-I did not modify the conductance of the voltage-gated potassium channel Kv10.1. This work proposes a new envenomating function of peptides from venoms of tarantulas, and establishes a new mechanism for venom-induced vasodilation.

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BACKGROUND: Topical treatments and botulinum toxin injections are valid options for the management of patients with chronic anal fissures (CAF), but little is known about the efficacy of these techniques in long-term follow-up. The aim of this meta-analysis was to evaluate the effectiveness, given to clinical outcomes, of medical treatments with calcium antagonists, nitroglycerin, and botulinum toxin on CAF treatment in adults. METHOD: A systemic review and meta-analysis developed according to PRISMA [PLoS Med. 2009 Jul 21;6(7):e1000100; BMJ. 2010 Mar 23;340:c332] and registered in PROSPERO (Registration number: CRD42020120386). A systematic literature search was conducted through MEDLINE, EMBASE, Web of Science, and Cochrane Library databases. Randomized control trials that compared medical treatment were identified; publications had to have a clinical definition of CAF with at least one of the following signs or symptoms: visible sphincter fibers at the base of the fissure, anal papillae, sentinel piles, and indurated margins. The symptoms had to be chronic for at least 4 weeks. Data were independently extracted for each study, and a meta-analysis was drawn using fixed- and random-effects models. RESULTS: 17 randomized trials met the inclusion criteria. Diltiazem showed a superior effect compared with glycerin (RR = 1.16 [95% CI = 1.05-1.30]; I2 = 18%) and with fewer adverse effects (RR = 0.13 [95% CI = 0.04-0.042]; I2 = 87%). Similar results were evidenced with the use of nifedipine compared with lidocaine (RR = 4.53 [95% CI = 2.99-6.86]; I2 = 28%). Botulinum toxin did not show statistically significant differences compared to glycerin (RR = 0.81 [95% CI = 0.02-29.36]; I2 = 93%) or isosorbide dinitrate (RR = 1.45 [95% CI = 0.32-6.54]; I2 = 85%). Regarding recurrence, nifedipine was superior to lidocaine (RR = 0.18 [95% CI = 0.08-0.44]; I2 = 31%). CONCLUSIONS: Calcium channel blockers performed well regarding the healing of CAF when compared to others in long-term follow-up. The superiority of botulinum toxin was not evidenced compared to topical treatments. More studies are needed to better assess recurrence rates.

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The Buthidae family of scorpions consists of arthropods with significant medical relevance, as their venom contains a diverse range of biomolecules, including neurotoxins that selectively target ion channels in cell membranes. These ion channels play a crucial role in regulating physiological processes, and any disturbance in their activity can result in channelopathies, which can lead to various diseases such as autoimmune, cardiovascular, immunological, neurological, and neoplastic conditions. Given the importance of ion channels, scorpion peptides represent a valuable resource for developing drugs with targeted specificity for these channels. This review provides a comprehensive overview of the structure and classification of ion channels, the action of scorpion toxins on these channels, and potential avenues for future research. Overall, this review highlights the significance of scorpion venom as a promising source for discovering novel drugs with therapeutic potential for treating channelopathies.

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ABSTRACT Idiopathic pulmonary arterial hypertension (PAH) patients with a positive response to acute vasodilator challenge and a clinical response to calcium channel blockers (CCBs) for at least one year are traditionally designated true responders. Nevertheless, little is known about a sustained response to CCBs over longer periods of time. We evaluated the loss of response to CCBs after long-term treatment in a cohort of idiopathic PAH patients previously classified as being true responders. Our data suggest that idiopathic PAH patients can lose clinical response to CCBs even after one year of clinical stability, reinforcing the need for constant multidimensional reevaluation to assess the need for targeted PAH therapies and to classify these patients correctly.

RESUMO Pacientes com hipertensão arterial pulmonar (HAP) idiopática com resposta positiva ao teste de vasorreatividade aguda e resposta clínica a bloqueadores dos canais de cálcio (BCC) durante no mínimo um ano são tradicionalmente denominados "respondedores verdadeiros". No entanto, pouco se sabe sobre a manutenção da resposta a BCC durante períodos mais longos. Avaliamos a perda de resposta a BCC após tratamento prolongado em uma coorte de pacientes com HAP idiopática previamente considerados respondedores verdadeiros. Nossos dados sugerem que pacientes com HAP idiopática podem deixar de apresentar resposta clínica a BCC mesmo depois de um ano de estabilidade clínica, reforçando a necessidade de reavaliação multidimensional constante para avaliar a necessidade de terapias específicas para HAP e classificar esses pacientes corretamente.

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Spider toxin SNX-482 is a cysteine-rich peptide that interferes with calcium channel activity by binding to voltage-sensing domains of the CaV2.3 subtype. Two mechanisms dominate the binding process of cysteine-rich peptides: direct binding from the aqueous phase or through lateral diffusion from the membrane, the so-called reduction in dimensionality mechanism. In this work, via coarse-grained and atomistic molecular dynamics simulations, we have systematically studied the spontaneous partitioning of SNX-482 with membranes of different anionic compositions and explored via diffusional analysis both binding mechanisms. Our simulations revealed a conserved protein patch that inserts in the membrane, a preference for binding towards partially negatively charged membranes, and that electrostatics guides membrane binding by incrementing and aligning the molecular dipole. Finally, diffusivity calculations showed that the toxin diffusion along the membrane plane is an order of magnitude slower than the aqueous phase suggesting that the critical factor in determining the SNX-482-CaV2.3 binding mechanism is the affinity between the membrane and SNX-482.

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The cannabinoid receptors (CB1/CB2) and the T-type calcium channels are involved in disorders associated with both physiological pain and depressive behaviors. Valuable pharmacological species carbazole derivatives such as the NMP-4, NMP-7, and NMP-181 (Neuro Molecular Production) regulate both biological entities. In this work, DFT calculations were performed to characterize theoretically their structural and chemical reactivity properties using the BP86/cc-pVTZ level of theory. The molecular orbital contributions and the chemical reactivity analysis reveal that a major participation of the carbazole group is in the donor-acceptor interactions of the NMP compounds. The DFT analysis on the NMP compounds provides insights into the relevant functional groups involved during the ligand-receptor interactions. Molecular docking analysis is used to reveal possible sites of interaction of the NMP compounds with the Cav3.2 calcium channel. The interaction energy values and reported experimental evidence indicate that the site denominated as "Pore-blocking", which is formed mainly by hydrophobic residues and the T586 residue, is a probable binding site for the NMP compounds.

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Resumo Fundamento: A Sauromatum guttatum (S. guttatum) é utilizado no tratamento de doenças do sangue e supostamente tem atividade espasmolítica através da inibição dos canais de Ca2+. Objetivos: O objetivo deste estudo foi investigar o potencial anti-hipertensivo de S. guttatum em modelo de rato Sprague-Dawley (SD) com hipertensão induzida por dieta com alto teor de sal (HIDATS). Métodos: Ratos SD foram divididos em normotensos, hipertensos e grupos tratados com verapamil e S. guttatum. Extrato bruto de S. guttatum (Sg.B) (100, 150 e 300 mg/kg/dia) e verapamil (5, 10 e 15 mg/kg/dia) foram administrados por via oral junto com NaCl. Anéis aórticos e faixas do átrio direito de ratos normotensos foram utilizados para investigar os mecanismos subjacentes. O nível de significância estatística adotado foi de 5%. Resultados: A pressão arterial média diminuiu nos grupos hipertensos tratados com Sg.B e verapamil de forma dose-dependente (p <0,001). No estudo de reatividade vascular, a acetilcolina induziu relaxamentos com valor CE50 de 0,6 µg/mL (0,3-1,0) em ratos hipertensos tratados com Sg.B (300 mg/kg), sugerindo preservação endotelial. Em aorta isolada de rato normotenso, o Sg.B exibiu vasorrelaxamento com valor de CE50 de 0,15 mg/mL (0,10-0,20), após ablação por desnudamento endotelial ou pré-tratamento com L-NAME e atropina. O tratamento com Sg.B causou relaxamento contra contrações induzidas por K+ alto, como o verapamil. O Sg.B mostrou efeitos inotrópicos (82%) e cronotrópicos (56%) negativos em preparações isoladas atriais de ratos reduzidas com atropina. A avaliação fitoquímica indicou a presença de alcaloides, flavonoides e taninos. Conclusão: O S. guttatum possui efeito vasodilatador através da preservação da função endotelial, liberação de NO mediada pelo receptor muscarínico e inibição do movimento de Ca2+, enquanto o efeito depressor do miocárdio atrial pode estar ligado ao receptor muscarínico. Esses achados fornecem a base farmacológica para o uso do extrato de S. guttatum como um medicamento anti-hipertensivo.

Abstract Background: Sauromatum guttatum (S. guttatum) is used in the treatment of blood disorders and reportedly has a spasmolytic activity through Ca2+ channel inhibition. Objectives: The aim of this study was to investigate the antihypertensive potential of S. guttatum in high salt-induced hypertensive Sprague-Dawley (SD) rat model (HSHRs). Methods: SD rats were divided into normotensive, hypertensive, S. guttatum and verapamil treated groups. S. guttatum crude extract (Sg.Cr) (100, 150 and 300 mg/kg/day) and verapamil (5, 10 and 15 mg/kg/day) were administered orally along with NaCl. Aortic rings and right atrial strips from normotensive rats were used to investigate the underlying mechanisms. The level of statistical significance was set at 5%. Results: Mean arterial pressure decreased in the Sg.Cr and verapamil-treated hypertensive groups in a dose-dependent manner (p < 0.001). In the vascular reactivity study, acetylcholine induced relaxations with an EC50 value of 0.6 µg/mL (0.3-1.0) in Sg.Cr-treated hypertensive rats (300 mg/kg), suggesting endothelial preservation. In isolated normotensive rat aorta, Sg.Cr-treated rats showed vasorelaxation with an EC50 value of 0.15 mg/mL (0.10-0.20), ablated by endothelial denudation or pretreatment with L-NAME and atropine. Sg.Cr treatment caused relaxation against high K+-induced contractions, like verapamil. Sg.Cr showed negative inotropic (82%) and chronotropic effects (56%) in isolated rat atrial preparations reduced with atropine. The phytochemical investigation indicated presence of alkaloids, flavonoids and tannins. Conclusion: S. guttatum has a vasodilatory effect through endothelial function preservation, muscarinic receptor-mediated NO release and Ca2+ movement inhibition, while atrial myocardial depressant effect can be linked to the muscarinic receptor. These findings provide pharmacological base for using S. guttatum extract as an antihypertensive medication.

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La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of high-dose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution

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Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of highdose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution.

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

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Peptides isolated from spider venoms are of pharmacological interest due to their neurotoxic activity, acting on voltage-dependent ion channels present in different types of human body tissues. Three peptide toxins titled as Ap2, Ap3 and Ap5 were purified by RP-HPLC from Acanthoscurria paulensis venom. They were partially sequenced by MALDI In-source Decay method and their sequences were completed and confirmed by transcriptome analysis of the venom gland. The Ap2, Ap3 and Ap5 peptides have, respectively, 42, 41 and 46 amino acid residues, and experimental molecular masses of 4886.3, 4883.7 and 5454.7 Da, with the Ap2 peptide presenting an amidated C-terminus. Amongst the assayed channels - NaV1.1, NaV1.5, NaV1.7, CaV1.2, CaV2.1 and CaV2.2 - Ap2, Ap3 and Ap5 inhibited 20-30 % of CaV2.1 current at 1 µM concentration. Ap3 also inhibited sodium current in NaV1.1, Nav1.5 and Nav1.7 channels by 6.6 ± 1.91 % (p = 0.0276), 4.2 ± 1.09 % (p = 0.0185) and 16.05 ± 2.75 % (p = 0.0282), respectively. Considering that Ap2, Ap3 and Ap5 belong to the 'U'-unknown family of spider toxins, which has few descriptions of biological activity, the present work contributes to the knowledge of these peptides and demonstrates this potential as channel modulators.

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Schizophrenia exhibits up to 80% heritability. A number of genome wide association studies (GWAS) have repeatedly shown common variants in voltage-gated calcium (Cav) channel genes CACNA1C, CACNA1I and CACNA1G have a major contribution to the risk of the disease. More recently, studies using whole exome sequencing have also found that CACNA1B (Cav2.2 N-type) deletions and rare disruptive variants in CACNA1A (Cav2.1 P/Q-type) are associated with schizophrenia. The negative symptoms of schizophrenia include behavioural defects such as impaired memory, sleep and circadian rhythms. It is not known how variants in schizophrenia-associated genes contribute to cognitive and behavioural symptoms, thus hampering the development of treatment for schizophrenia symptoms. In order to address this knowledge gap, we studied behavioural phenotypes in a number of loss of function mutants for the Drosophila ortholog of the Cav2 gene family called cacophony (cac). cac mutants showed several behavioural features including decreased night-time sleep and hyperactivity similar to those reported in human patients. The change in timing of sleep-wake cycles suggested disrupted circadian rhythms, with the loss of night-time sleep being caused by loss of cac just in the circadian clock neurons. These animals also showed a reduction in rhythmic circadian behaviour a phenotype that also could be mapped to the central clock. Furthermore, reduction of cac just in the clock resulted in a lengthening of the 24 h period. In order to understand how loss of Cav2 function may lead to cognitive deficits and underlying cellular pathophysiology we targeted loss of function of cac to the memory centre of the fly, called the mushroom bodies (MB). This manipulation was sufficient to cause reduction in both short- and intermediate-term associative memory. Memory impairment was accompanied by a decrease in Ca2+ transients in response to a depolarizing stimulus, imaged in the MB presynaptic terminals. This work shows loss of cac Cav2 channel function alone causes a number of cognitive and behavioural deficits and underlying reduced neuronal Ca2+ transients, establishing Drosophila as a high-throughput in vivo genetic model to study the Cav channel pathophysiology related to schizophrenia.

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