Search Results (40)

The aim of this work is to introduce a computer science solution to manage emotions and affections and connect them to the causes as in humans. The scientific foundation of this work lies in the ability to model the affective and emotional states of an individual or artificial intelligence (AI). Then, in this study, we go a step further by exploring how to extend this capability by linking it to the underlying causes—specifically, by establishing a connection between emotions, affective states, and neurotransmitter activities. The methods used in this study pertain to decision support systems based on complexity theory. Specifically, for the training of the platform to study the link between emotions/affections and neurotransmitters, an electroencephalogram (EEG) acquisition module is integrated into the platform. As a result, this solution provides the bedrock for next-generation AI, i.e., artificial rational–emotive decision-makers. In addition, this research studies the connection of EEG data with neurotransmitters’ activity, opening pathways to applications such as emotional monitoring, mental health, and brain–computer interfaces, adding to cognitively and emotionally enriched AI. The main result of this study is a platform able to manage artificial neurotransmitters such as adrenaline, GABA, dopamine, serotonin, oxytocin, endorphins, and the hormone cortisol for emulating and motivating emotive and affective states. In conclusion, this study highlights the following: (i) the possibility of conducting indirect measurements of emotional states based on EEG data, (ii) the development of a framework capable of generating a wide spectrum of emotional states by modulating neurotransmitter levels within a defined discrete range, and (iii) the ability to establish a connection between neurotransmitters (causes) and emotional states (effects). Full article

Out-of-hospital cardiac arrest (OHCA) mortality remains alarmingly high in most countries. The majority of pharmacological attempts to improve outcomes have failed. Randomized trials have shown limited survival benefits with vasopressin, fibrinolysis, amiodarone, or lidocaine. Even the benefits of adrenaline remain a matter of debate. In this context, relying on technology may seem appealing. However, technological strategies have also yielded disappointing results. This is exemplified by automated external chest compression devices. When first introduced, theoretical models, animal studies, and early clinical trials suggested they could improve survival. Yet, randomized trials failed to confirm this benefit. Similarly, to date, extracorporeal membrane oxygenation (ECMO), therapeutic hypothermia, and primary angioplasty have demonstrated inconsistent survival advantage. Other technological innovations continue to be explored, such as artificial intelligence to improve the diagnosis of cardiac arrest during emergency calls, mobile applications to dispatch citizen responders to patients in cardiac arrest, geolocation of defibrillators, and even the delivery of defibrillators via drones. Nevertheless, it is clear that the focus and investment should prioritize the initial links in the chain of survival: early alerting, chest compressions, and defibrillation. Significant improvements in these critical steps can be achieved through the education of children. Modern technological tools must be leveraged to enhance this training by incorporating gamification and democratizing access to education. These strategies hold the potential to fundamentally improve the management of cardiac arrest. Full article

Background: Out-of-hospital cardiac arrest (OHCA) is a critical health issue with survival influenced by multiple factors. This study analyzed resuscitation outcomes at the County Clinical Emergency Hospital of Sibiu, Romania, during pre-COVID-19 and pandemic periods. Methods: A retrospective analysis of 508 OHCA patients (2017–2020) assessed the return of spontaneous circulation (ROSC) as the primary endpoint. Statistical methods included decision tree analysis, logistic regression and ROC curve analysis to evaluate the predictive value of adrenaline dose and patient factors. Results: The mortality rate was 68.7%, with non-shockable rhythms predominant among fatalities. Rural patients, though younger, had lower ROSC rates than urban counterparts. Logistic regression showed that lower adrenaline doses (≤4 mg, OR 11.835 [95% CI: 6.726–20.27]; 4–6 mg, OR 2.990 [95% CI: 1.773–5.042]) were associated with better ROSC outcomes. Conclusions: A multivariable model (AUC = 0.773) incorporating demographics and pandemic status outperformed adrenaline dose alone (AUC = 0.711). Full article

Aim: Cardiac arrhythmias are among the most important pathologies that cause sudden death. The exploration of new therapeutic options against arrhythmias with low undesirable effects is of paramount importance. Methods: However, the convenient and typical animal model for screening the potential lead compound becomes a very critical modality, particularly in anti-arrhythmia. In this study, mice were intraperitoneally (i.p.) injected with BaCl₂, CaCl₂, and adrenaline to induce arrhythmia, and simultaneously compared with BaCl₂-induced rats. Results: Electrocardiogram (ECG) showed that the majority of mice repeatedly developed ventricular bigeminy, ventricular tachycardia (VT), and ventricular fibrillation (VF) after BaCl₂-injection as seen in rats. The ECG of mice developed ventricular bigeminy and VT after CaCl₂ and AT after adrenaline i.p. injection. Additionally, acute cardiac arrhythmia after BaCl₂ i.p. injection could be reverted by drugs (lidocaine and amiodarone) administration. Additionally, the different routes of administration for various chemical-induced arrhythmia in both mice and rats were also retrieved from PubMed and summarized. Comparing this approach with previous studies after the literature review reveals that arrhythmia of BaCl₂-induced i.p. mice is compatible with the induction of other routes. Conclusions: This study brings an alternative experimental model to investigate antiarrhythmic theories and provides a promising approach to discovering new interventions for acute arrhythmias. Full article

After Alzheimer’s disease, Parkinson’s disease (PD) is the second most prevalent neurological illness. Clinically, it is defined by parkinsonism, which includes stiffness, bradykinesia, resting tremor, and postural instability. Pathologically, it is characterized by the loss of substantia nigra neurons. Monoamine oxidases (MAO-A and MAO-B) are enzymes responsible for metabolizing neurotransmitters such as dopamine (DA) and adrenaline. Selective MAO-A or MAO-B inhibitors have been the focus of recent attempts to create MAO inhibitors. In addition, Parkinson’s disease can be effectively treated with MAO-B inhibitors. The objective is to elucidate the several types of interactions between enzymes and ligands and assess the stability of the resulting complexes. Various molecular modeling methods are used to study the inhibition of the enzyme MAO-B (PDB:4a79) involved in PD, including molecular docking, molecular dynamics, MOE software, and ADME prediction. Based on the findings, compound L30 and compound L38, the top contenders identified by molecular docking/dynamic simulations and with low energy scores, had low IC50 values (0.110 and 0.305 µM, respectively). The combination of the two outcomes from the earlier techniques demonstrates that the compounds L30 and L38 were chosen as the most effective MAO-B inhibitors and that they also satisfy the Lipinski, Veber, and Egan rules. They are also able to traverse the BBB. Furthermore, they may be utilized to create novel pharmaceutical medicines to treat individuals with PD. Full article

Nitroxides, stable synthetic free radicals, are promising antioxidants, showing many beneficial effects both at the cellular level and in animal studies. However, the cells are usually treated with high millimolar concentrations of nitroxides which are not relevant to the concentrations that could be attained in vivo. This paper aimed to examine the effects of low (≤10 μM) concentrations of three nitroxides, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), 4-hydroxy-TEMPO (TEMPOL) and 4-amino-TEMPO (TEMPAMINE), in pure chemical systems and on SH-SY5Y cells transfected with the human tau protein (TAU cells), a model of chronic cellular oxidative stress, and transfected with the empty plasmid (EP cells). All nitroxides were active in antioxidant-activity tests except for the 2,2′-azinobis-(3-ethylbenzthiazolin-6-sulfonate) radical (ABTS^•) decolorization assay and reduced Fe³⁺, inhibited autoxidation of adrenalin and pyrogallol and oxidation of dihydrorhodamine123 by 3-morpholino-sydnonimine SIN-1. TEMPO protected against fluorescein bleaching from hypochlorite, but TEMPAMINE enhanced the bleaching. Nitroxides showed no cytotoxicity and were reduced by the cells to non-paramagnetic derivatives. They decreased the level of reactive oxygen species, depleted glutathione, and increased mitochondrial-membrane potential in both types of cells, and increased lipid peroxidation in TAU cells. These results demonstrate that even at low micromolar concentrations nitroxides can affect the cellular redox equilibrium and other biochemical parameters. Full article

As an alternative to animal use, computer simulations are useful for predicting pharmacokinetics and cardiovascular activities. For this purpose, we constructed a statistical model to simulate the effects of local anesthetic agents. To train the model, animal experiments were performed on 6-week-old male Hartley guinea pigs. Firstly, the guinea pigs’ backs were shaved, then local anesthetic agents were subcutaneously injected, with subsequent stimulation of the anesthetized site with a needle six times at regular intervals. The number of reactions (score value) was counted. In this statistical model, the probability of reacting to needle stimulation was calculated using the elapsed time, type of local anesthetic agent, and presence or absence of adrenaline. Score values were assumed to follow a binomial distribution at the calculated probability. Parameters were estimated using the Bayesian hierarchical model and Hamiltonian Monte Carlo method. The predicted curves using the estimated parameters fitted well the observed animal values. When score values were predicted using randomly generated parameters, the median of duration was similar between animal experiments and simulations (Procaine: 55 min vs. 50 min, Lidocaine: both 60 min, and Mepivacaine: both 85 min). This approach effectively modeled the effects of local anesthetic agents. It is possible to create the simulator using the parameter values estimated in this study. Full article

Superoxide is the primary active oxygen form produced in living organisms. Because of superoxide anion radical formation during epinephrine oxidation in alkaline medium, this system is offered in some works for antioxidant activity analysis, however, without enough physicochemical justification. Therefore, the task of developing reliable methods for analyzing the superoxide inhibition activity of various objects is very urgent. In this work, a kinetic model of epinephrine autoxidation in an alkaline medium in the presence of antioxidants of plant origin is proposed. The participation of chain reactions with long oxidation chains in this process is revealed. The limiting stage of the process is a one-electron reduction of oxygen by the anionic forms of the phenolic hydroxyls of epinephrine. The appearance of the absorption maximum at a wavelength of 347 nm during epinephrine autoxidation is associated with adrenolutin formation, which is confirmed by HPLC/UV/MS. No adduct formation between phenolic antioxidants and epinephrine oxidation products was found. The complex U-shaped character of epinephrine autoxidation rate dependence on the content of antioxidants in the reaction system was shown. The study of the kinetics of epinephrine autoxidation in the presence of an individual phenolic plant superoxide inhibitor, chlorogenic acid, was carried out for the first time. The inhibitory effect of yarrow, chamomile, and bur beggar-ticks plant extracts in the adrenaline system was examined. Full article

The neurotoxin β-N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by cyanobacteria. Non-neuronal toxicity of BMAA is poorly studied with a reported increase in reactive oxygen species and a decrease in the antioxidant capacity of liver, kidney, and colorectal adenocarcinoma cells. The aim of this research is to study the toxicity of BMAA (0.1–1 mM) on mitochondria and submitochondrial particles with ATPase activity, on the semicarbazide-sensitive amino oxidases (SSAOs) activity of rat liver, and on an in vitro model containing functionally active excitable tissues—regularly contracting heart muscle preparation with a preserved autonomic innervation. For the first time the BMAA-dependent inhibition of SSAO activity, the elimination of the positive inotropic effect of adrenergic innervation, and the direct and reversible inhibition of adrenaline signaling in ventricular myocytes with 1 mM BMAA were observed. Additionally, it is confirmed that 1 mM BMAA can activate mitochondrial ATPase indirectly. It is concluded that a higher dose of BMAA may influence multiple physiological and pathological processes as it slows down the degradation of biogenic amines, downregulates the sympathetic neuromediation, and embarrasses the cell signaling of adrenergic receptors. Full article

Inherited disorders of biogenic amine metabolism are genetically determined conditions resulting in dysfunctions or lack of enzymes involved in the synthesis, degradation, or transport of dopamine, serotonin, adrenaline/noradrenaline, and their metabolites or defects of their cofactor or chaperone biosynthesis. They represent a group of treatable diseases presenting with complex patterns of movement disorders (dystonia, oculogyric crises, severe/hypokinetic syndrome, myoclonic jerks, and tremors) associated with a delay in the emergence of postural reactions, global development delay, and autonomic dysregulation. The earlier the disease manifests, the more severe and widespread the impaired motor functions. Diagnosis mainly depends on measuring neurotransmitter metabolites in cerebrospinal fluid that may address the genetic confirmation. Correlations between the severity of phenotypes and genotypes may vary remarkably among the different diseases. Traditional pharmacological strategies are not disease-modifying in most cases. Gene therapy has provided promising results in patients with DYT-DDC and in vitro models of DYT/PARK-SLC6A3. The rarity of these diseases, combined with limited knowledge of their clinical, biochemical, and molecular genetic features, frequently leads to misdiagnosis or significant diagnostic delays. This review provides updates on these aspects with a final outlook on future perspectives. Full article

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α₁-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α₁- but not α₂-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α₁-adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs. Full article

Arrhythmia, an irregular heartbeat, might be a life-threatening condition but also a risk factor for stroke or worsen the prognosis after myocardial infarction. The limited efficacy and proarrhythmic potential of the available drugs require searching for new, more effective, and safer pharmacotherapies. Studies indicate that the blockade of α₁-adrenoceptors could be effective in treating heart rhythm abnormalities. In this study, we aimed to assess the antiarrhythmic and hypotensive potential of HBK-10, a novel 2-methoxyphenylpiperazine derivative, as well as its binding to the selected adrenergic receptors. Radioligand binding studies demonstrated that HBK-10 showed a high affinity for α₁ but not for α₂ or β₁ receptors. Next, we evaluated the ability of HBK-10 to protect against an adrenaline-induced arrhythmia in rats. The compound showed potent prophylactic antiarrhythmic properties in this arrhythmia model. Notably, the compound did not show proarrhythmic potential in normotensive rats since it did not influence the ECG parameters at antiarrhythmic doses. Finally, the compound showed hypotensive properties in rats, which were not observed after coadministration with adrenaline, noradrenaline, or methoxamine, which suggests α₁-adrenolytic properties of HBK-10. Our results confirm that compounds with a 2-methoxyphenylpiperazine group show a high affinity for α₁-adrenoceptors and a significant antiarrhythmic effect. Given the promising results of our study, further evaluation of HBK-10 is necessary to unravel the mechanisms behind its pharmacological effects and evaluate the safety profile. Full article

Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α₁-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α₁-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β₁-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α₁-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs. Full article

The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to $\mathsf{\beta }$₂-adrenergic receptor ($\mathsf{\beta }$₂AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human $\mathsf{\beta }$₂AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible $\mathsf{\beta }$₂AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into $\mathsf{\beta }$₂AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 $\mathsf{\mu }$s MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF. Full article

Background: Systemic arterial hypertension, which is associated with an increased risk of cardiovascular disease(CVD), is the most significant modifiable risk factor for mortality and morbidity worldwide. WHO has recognized Unanipathy as an alternate system of medicine. The aim of the present study is to investigate the anti-hypertensive activity of some selected unani formulations using L-NAME model. Method: Group I or hypertensive control group: L-NAME administered for 7 days and left for the next 7 days; Group II or KASgroup: L-NAME administered (i.p) for 7 days and L-NAME + KAS (1000 mg/kg b.w) for the next 7 days; Group III or DMM group: L-NAME administered (i.p) for 7 days and L-NAME + DMM (2000 mg/kg b.w) for the next 7 days; Group IV or MSR group: L-NAME administered (i.p) for 7 days and L-NAME + MSR (300 mg/kg b.w) for the next 7 days; Group V or HJ group: L-NAME administered (i.p) for 7 days and L-NAME + HJ (113 mg/kg b.w) for the next 7 days; Group VI or KGS group: L-NAME administered (i.p) for 7 days and L-NAME +KGS (2000 mg/kg b.w) for the next 7 days. Non-invasive systolic blood pressure and RR-interval (ECG) was measured. Plasma was investigated forsodium, potassium, nitrite, ANP, adrenaline, noradrenaline and aldosterone on day 0, 7 and 14 using LC-MS/MS. Result: Treatment showed a non-significant lowreduction in SBP (systolic blood pressure) of KAS, MSR and HJ while that of DMM was quite significant (p < 0.05), but in the case of KGS, SBP increased. DMM on day 14 significantly (p < 0.05) reduced plasma nitrite while no significant plasma Na+ was noted. In the case of both DMM and KGS, potassium increased significantly (p < 0.05) on day 14. No significant changes in plasma ANP and aldosterone was observed against DMM and KGS while blood levels of adrenaline and noradrenaline significantly (p < 0.05) changed. No significant change in body weight was found. Conclusions: L-NAME KAS, MSR and HJ showed no change in SBP while DMM showed a significant reduction in SBP with decreased plasma nitrite. Probably, DMM may have anti-hypertensive activity mediated through NO inhibition while KGS may involve central sympathomimetic action. Full article