Probiotics and the reduction of SARS-CoV-2 infection through regulation of host cell calcium dynamics.

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.

Isradipine, an L-type calcium channel blocker, attenuates cocaine effects in mice by reducing central glutamate release.

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.

SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.

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.

Effects of intravenous administration of recombinant Phα1ß toxin in a mouse model of fibromyalgia.

This study investigated the effects of intravenous (iv) administration of recombinant Phα1ß toxin, pregabalin, and diclofenac by the intrathecal route using an animal model fibromyalgia (FM). The reserpine administration (0.25 mg/kg s. c) once daily for three consecutive days significantly induced hyperalgesia, immobility time, and sucrose consumption in mice on the 4th day. Reserpine caused hyperalgesia on the mechanical and thermal hyperalgesia on the 4th day was reverted by recombinant Phα1ß (0.2 mg/kg iv) and pregabalin (1.25 µmol/site i. t) treatments. In contrast, diclofenac (215 nmol/site i. t) was ineffective. Recombinant Phα1ß toxin, pregabalin, and diclofenac did not affect the depressive-like behavioural effect induced by reserpine on mice during the forced swim and sucrose consumption tests. The data confirmed the analgesic effect of the recombinant Phα1ß toxin administered intravenously in a fibromyalgia mouse model.

SMART Syndrome Identification and Successful Treatment.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare late complication of brain irradiation. Patients commonly present recurrent attacks of headaches, seizures, and paroxysmal focal neurological deficits including aphasia, negligence, or hemianopsia. We report a 41-year-old male patient admitted to our emergency room with a reduced level of consciousness and global aphasia. One month prior to admission, he started with frequent headache attacks of moderate intensity and paroxysmal behavioral alterations, advancing to confusion, gait instability, language impairment, and somnolence. He had a history of medulloblastoma treated with surgical resection followed by craniospinal irradiation 21 years before symptom onset. After excluding more frequent causes for the patient's symptoms along with a suggestive image pattern, we started treatment for SMART syndrome with high-dose corticosteroid and calcium channel blocker verapamil. The patient gradually improved his level of consciousness and recovered from aphasia and gait instability without new seizures or neuropsychiatric symptoms. Follow-up brain magnetic resonance imaging showed resolution of the typical findings. This case displays a successful clinical evolution of a patient treated for SMART syndrome in which identification of previous radiation treatment, exclusion of other etiologies, and prompt treatment institution were key for effectively tackling this disease.

Bioenergetics impairment of Trypanosoma cruzi by the antihypertensive manidipine: A drug repurposing strategy.

Considering the lack of effective and safe therapy for the treatment of Chagas disease, the antihypertensive drug manidipine (MDP) was in vitro evaluated against Trypanosoma cruzi. The bioenergetics of trypomastigotes was studied in the presence of the drug using fluorimetric and luminescent assays. Manidipine showed a potent antiparasitic activity, with IC50 values of 0.1 µM (intracellular amastigotes) and 3 µM (trypomastigotes), resulting in a promising selectivity index against the amastigotes (>1459). Using fluorimetric analysis, the drug showed depolarisation of the electric potential of the plasma membrane with no alteration of the permeability. A decrease in ATP levels suggested a bioenergetic alteration of the mitochondria, which was confirmed by the depolarisation of the mitochondrial membrane potential and a slight increase of the ROS levels. This is the first study to show the promising in vitro effectiveness of the antihypertensive MDP against T. cruzi, which may represent a candidate for future investigations in animal models.

Long-chain fatty dihydropyridines: Docking calcium channel studies and antihypertensive activity.

AIMS: From the synthesis of 43 lipophilic dihydropyridines, the aim of this study was to verify whether the new dihydropyridines have calcium channel affinity using coupling studies and to determine antihypertensive and antioxidant properties, as well as toxicology and toxicity nifedipine and three new compounds, were chosen from the previous results. MATERIALS AND METHODS: The animals were treated for 56 days, 28 days with N (ω) -nitro-L-arginine methyl ester to induce hypertension, and then treated for another 28 days with the new di- hydropyridine and the standard drug nifedipine. Throughout the treatment the animals had their blood pressure measured and their heart rate checked by pletysmography. After treatment the animals were euthanised, blood samples were collected for creatine kinase and urea analysis, and the brain, heart and liver were collected for oxidative status analysis (quantification of reactive oxygen species, total antioxidant capacity, and lipid peroxidation). KEY FINDINGS: Compounds 2c, and 9a, and nifedipine significantly reduced blood pressure to control group levels. The tachycardia caused by the induction of hypertension was reversed by 2c and 9a compounds. Regarding oxidative stress analyzes, the compounds that had the best performances were also 2c and 9a. Overall the results demonstrate that two of the three new dihydropyridines tested demonstrated performance equal to or superior to the standard drug nifedipine. SIGNIFICANCE: In this study, for the first time, docking was applied to analyse 43 fatty dihydropyridines regarding their calcium channel binding. Afterwards, three fatty dihydropyridines were chosen and their antihypertensive and antioxidant properties.

Evaluation of smooth muscle relaxant potential of Bismarckia nobilis (Hildebr. & Wendl.) in diarrhea, hypertension and asthma by ex-vivo and in-vivo method / Evaluación del potencial relajante en músculo liso de Bismarckia nobilis (Hildebr. & Wendl.) en diarrea, hipertensión y asma por métodos ex vivo e in vivo

To explore the mechanistic basis behind smooth muscle relaxant prospective of Bismarckia nobilis in gastrointestinal, respiratory and cardiovascular ailments. The methanolic extract of B. nobilis and sub-fractions have been evaluated in vitro rabbit isolated tissues, in vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice. The B. nobilis extract relaxed spontaneous and K+(80 mM)- induced contractions in rabbit isolated jejunum preparations, CCh (1 µM) and K+ (80 mM)-induced contractions in tracheal and bladder preparations, PE (1 µM) and K+ (80 mM)-induced concentrations in aorta preparations, likewise verapamil. Spasmolytic activity of dichloromethane fraction is stronger as compared to aqueous fraction. In vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice further supported spasmolytic activity. B. nobilis extract possess anti-spasmodic, anti-diarrheal, airway relaxant and vasodilator activities possible mediated through calcium channel blocking mechanism, justifying therapeutic utility of B. nobilis in diarrhea, asthma and hypertension.

El objetivo de trabajo fue explorar el mecanismo de acción relacionado con el efecto relajante del músculo liso inducido por Bismarckia nobilis (B. nobilis) en enfermedades gastrointestinales, respiratorias y cardiovasculares. El extracto metanólico de B. nobilis y subfracciones fue evaluado in vitro en tejidos aislados de conejos. Además se evaluó diarrea in vivo inducida con aceite de ricino en ratas y la actividad de harina de carbón vegetal en ratones. El extracto de B. nobilis relajó tanto las contracciones espontáneas como las inducidas por K+(80 mM) en preparaciones de yeyuno aisladas de conejos, las contracciones inducidas por PE (1 µM) y K+(80 mM) inducidas en preparaciones de aorta; de manera similar a verapamilo. La actividad espasmolítica de la fracción de diclorometano es más potente en comparación con la fracción acuosa. La diarrea inducida in vivo por el aceite de ricino en ratas y la actividad de la harina de carbón vegetal en ratones apoyaron aún más la actividad espasmolítica. El extracto de B. nobilis posee actividades antiespasmódicas, antidiarreicas, relajantes de las vías respiratorias y vasodilatadoras, posibles a través del mecanismo de bloqueo de los canales de calcio, lo que justifica la utilidad terapéutica de B. nobilis en la diarrea, el asma y la hipertensión.

Hiperplasia gengival induzida por anlodipina: relato de caso em dois cães / Gengival hyperplasia induced by amlodipine: case report of 2 dogs / Hiperplasia gingival inducido por amlodipina: reporte de 2 casos en perros

Dois cães, SRD, de 14 e 8 anos, pesando 26,3 e 34kg, apresentaram hiperplasia gengival após quatro meses de uso de 0,1 mg por quilo a cada 12 horas de anlodipina para controle de hipertensão. Ambos pacientes apresentavam sialorreia, halitose intensa e dificuldade em se alimentar. O tratamento instituído foi a gengivectomia e a substituição da anlodipina. A anlodipina é um bloqueador de canal de cálcio. Essa classe de medicamentos pode induzir a hiperplasia gengival, porém casos envolvendo a anlodipina são raros ou pouco relatados. A suspensão da anlodipina normalmente leva a regressão total da hiperplasia gengival. O objetivo desse relato é ressaltar a importância do tratamento cirúrgico em casos onde a hiperplasia gengival causa desconforto ao animal.(AU)

Two 14 and 8 years, with 26,3 and 34 kg, mongrel dogs, developed gingival hyperplasia after 4 months of 0.1mg per kg every 12 hours of amlodipine for systemic hypertension control. The patients presented drooling, severe halitosis and difficulty in feeding itself. The treatment chosen was gingivectomy and replacement of amlodipine. Amlodipine is a calcium channel blocker. This class of drugs can induce gingival hyperplasia, but cases involving amlodipine are rare or underreported. The suspension of amlodipine usually leads to complete regression of gingival hyperplasia. The objective of this report is to highlight the importance of surgical treatment in cases where the gingival hyperplasia causes discomfort to the animal.(AU)

Dos perros mestizos, 14 y 8 anos con peso de 26,3 e 34 kg, tenían hiperplasia gingival después de 4 meses de uso de 0,1 mg por kg cada 12 horas de amlodipino para el control de la hipertensión. Los pacientes tenían sialorreia, halitosis severa y dificultad en la alimentación durante 3 días. El tratamiento se realizó por gingivectomía y sustitución de amlodipino. El amlodipino es un bloqueador de los canales de calcio. Esta clase de medicamentos puede inducir hiperplasia gingival, pero los casos de amlodipino son raros o no reportado. La suspensión de amlodipino lo general conduce a la completa regresión de la hiperplasia gingival. El objetivo de este informe es poner de relieve la importancia del tratamiento quirúrgico en los casos en que la hiperplasia gingival causa malestar al animal.(AU)

Hiperplasia gengival induzida por anlodipina: relato de caso em dois cães / Gengival hyperplasia induced by amlodipine: case report of 2 dogs / Hiperplasia gingival inducido por amlodipina: reporte de 2 casos en perros

Dois cães, SRD, de 14 e 8 anos, pesando 26,3 e 34kg, apresentaram hiperplasia gengival após quatro meses de uso de 0,1 mg por quilo a cada 12 horas de anlodipina para controle de hipertensão. Ambos pacientes apresentavam sialorreia, halitose intensa e dificuldade em se alimentar. O tratamento instituído foi a gengivectomia e a substituição da anlodipina. A anlodipina é um bloqueador de canal de cálcio. Essa classe de medicamentos pode induzir a hiperplasia gengival, porém casos envolvendo a anlodipina são raros ou pouco relatados. A suspensão da anlodipina normalmente leva a regressão total da hiperplasia gengival. O objetivo desse relato é ressaltar a importância do tratamento cirúrgico em casos onde a hiperplasia gengival causa desconforto ao animal.

Two 14 and 8 years, with 26,3 and 34 kg, mongrel dogs, developed gingival hyperplasia after 4 months of 0.1mg per kg every 12 hours of amlodipine for systemic hypertension control. The patients presented drooling, severe halitosis and difficulty in feeding itself. The treatment chosen was gingivectomy and replacement of amlodipine. Amlodipine is a calcium channel blocker. This class of drugs can induce gingival hyperplasia, but cases involving amlodipine are rare or underreported. The suspension of amlodipine usually leads to complete regression of gingival hyperplasia. The objective of this report is to highlight the importance of surgical treatment in cases where the gingival hyperplasia causes discomfort to the animal.

Dos perros mestizos, 14 y 8 anos con peso de 26,3 e 34 kg, tenían hiperplasia gingival después de 4 meses de uso de 0,1 mg por kg cada 12 horas de amlodipino para el control de la hipertensión. Los pacientes tenían sialorreia, halitosis severa y dificultad en la alimentación durante 3 días. El tratamiento se realizó por gingivectomía y sustitución de amlodipino. El amlodipino es un bloqueador de los canales de calcio. Esta clase de medicamentos puede inducir hiperplasia gingival, pero los casos de amlodipino son raros o no reportado. La suspensión de amlodipino lo general conduce a la completa regresión de la hiperplasia gingival. El objetivo de este informe es poner de relieve la importancia del tratamiento quirúrgico en los casos en que la hiperplasia gingival causa malestar al animal.

Action of Phα1ß, a peptide from the venom of the spider Phoneutria nigriventer, on the analgesic and adverse effects caused by morphine in mice.

UNLABELLED: Opioids are standard therapy for the treatment of pain; however, adverse effects limit their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia, but their effect on opioid-induced side effects is little known. Thus, the goal of this study was to evaluate the action of the peptide Phα1ß, a voltage-gated calcium channel blocker, on the antinociceptive and adverse effects produced by morphine in mice. A single administration of morphine (3-10 mg/kg) was able to reduce heat nociception as well as decrease gastrointestinal transit. The antinociception caused by a single injection of morphine was slightly increased by an intrathecal injection of Phα1ß (30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal syndrome, and constipation, and the Phα1ß (.1-30 pmol/site, intrathecal) was able to reverse these effects. Finally, the effects produced by the native form of Phα1ß were fully mimicked by a recombinant version of this peptide. Taken together, these data show that Phα1ß was effective in potentiating the analgesia caused by a single dose of morphine as well as in reducing tolerance and the adverse effects induced by repeated administration of morphine, indicating its potential use as an adjuvant drug in combination with opioids. PERSPECTIVE: This article presents preclinical evidence for a useful adjuvant drug in opioid treatment. Phα1ß, a peptide calcium channel blocker, could be used not only to potentiate morphine analgesia but also to reduce the adverse effects caused by repeated administration of morphine.

Calcium influx through L-type channels attenuates skeletal muscle contraction via inhibition of adenylyl cyclases.

Skeletal muscle contraction is triggered by acetylcholine induced release of Ca(2+) from sarcoplasmic reticulum. Although this signaling pathway is independent of extracellular Ca(2+), L-type voltage-gated calcium channel (Cav) blockers have inotropic effects on frog skeletal muscles which occur by an unknown mechanism. Taking into account that skeletal muscle fiber expresses Ca(+2)-sensitive adenylyl cyclase (AC) isoforms and that cAMP is able to increase skeletal muscle contraction force, we investigated the role of Ca(2+) influx on mouse skeletal muscle contraction and the putative crosstalk between extracellular Ca(2+) and intracellular cAMP signaling pathways. The effects of Cav blockers (verapamil and nifedipine) and extracellular Ca(2+) chelator EGTA were evaluated on isometric contractility of mouse diaphragm muscle under direct electrical stimulus (supramaximal voltage, 2 ms, 0.1 Hz). Production of cAMP was evaluated by radiometric assay while Ca(2+) transients were assessed by confocal microscopy using L6 cells loaded with fluo-4/AM. Ca(2+) channel blockers verapamil and nifedipine had positive inotropic effect, which was mimicked by removal of extracellular Ca(+2) with EGTA or Ca(2+)-free Tyrode. While phosphodiesterase inhibitor IBMX potentiates verapamil positive inotropic effect, it was abolished by AC inhibitors SQ22536 and NYK80. Finally, the inotropic effect of verapamil was associated with increased intracellular cAMP content and mobilization of intracellular Ca(2+), indicating that positive inotropic effects of Ca(2+) blockers depend on cAMP formation. Together, our results show that extracellular Ca(2+) modulates skeletal muscle contraction, through inhibition of Ca(2+)-sensitive AC. The cross-talk between extracellular calcium and cAMP-dependent signaling pathways appears to regulate the extent of skeletal muscle contraction responses.

Hipertrofia gengival induzida por anlodipina: [revisão] / Amlodipine induced gingival overgrowth: [review]

JUSTIFICATIVA E OBJETIVOS: A hipertrofia gengival (HG) é reconhecidamente um grave efeito adverso a medicamentos, frequentemente encontrado em pacientes em uso de imunossupressores, anticonvulsivantes ou anti-hipertensivos. Nesta última classe, se destaca a nifedipina, porém tem sido crescente o númerode casos secundários ao uso da anlodipina. O objetivo deste estudo foi observar na literatura os dados existentes sobre a epidemiologia, características clínicas e histopatológicas, a prevenção e o tratamento da HG associada a este fármaco. CONTEÚDO: A coleta de dados foi realizada através dos Bancos de Dados BIREME, Pubmed e Medline. As palavras pesquisadas foram: aumento gengival, hipertrofia gengival, hiperplasia gengival, amlodipine induced gingival overgrowth, gingival overgrowth induced by calcium channel blockers, drug induced gingival overgrowth. No bando de dados BIREME foram encontrados 24 artigos referentes ao assunto pesquisado, na Pubmed e Medline foram encontrados 47 artigos pertinentes ao contexto enfocado. Do total, foram utilizados 34 artigos na revisão de literatura. CONCLUSÃO: A anlodipina é um fármaco que comprovadamente atua no tecido gengival causando o seu aumento. Sendo assim, a HG induzida por este fármaco tem aspectos clínicos característicos e é uma reação adversa individualizada devido à influência multifatorial. Em razão do atual aumento do uso deste bloqueador de canal de cálcio, a incidência da HG torna-se cada vez mais crescente. Desta forma, por gerar comprometimento funcional e estético ao indivíduo acometido, é de suma importância o conhecimento desta condição pelos profissionais de saúde para que ocorra a correta identificação do quadro e o estabelecimento precoce de uma conduta terapêutica adequada.

BACKGROUND AND OBJECTIVES: Gingival hyperplasia(GH) is admittedly a severe adverse effect of medications, frequently found in the immunosupressors, anticonvulsivants or antihypertensives users. Among this last class of medications, nifedipine is featured, but adverse effects due amlodipine using have been increasing. The aim of this study was to examine the existing data on the literature about epidemiology, clinical and histopathological features, prevention and treatment of GH due this medication. CONTENTS: The data collection was performed through BIREME, Pubmed and Medline databases. The words searched were: gingival enlargement, gingival hypertrophy, gingival hyperplasia, amlodipine induced gingival overgrowth, gingival overgrowth induced by calcium channel blockers, drug induced gingival overgrowth. In the BIREME databases were found 24 articles concerningon the topic searched, in Pubmed and Medline were found 47 relevant articles focused on the context. Totally, 34 articles ofthe literature review were used. CONCLUSION: Amlodipine is a drug that acts in the gingival tissue inducing its enlargement. Therefore, GH induced by thisdrug has typical clinical features and is an individualized adverse effect by the multifactorial influence. Due to the current increasein the use of calcium channel blocker, the incidence of GH becomes increasingly common. However, by the functional and esthetic commitment of the affected individual, is of high importance the knowledge about this condition by health professionals aiming the correct identification of this case and the early establishment of an appropriate treatment.