Influence of Prolonged Serotonin and Ergovaline Pre-Exposure on Vasoconstriction Ex Vivo

Ergot alkaloid mycotoxins interfere in many functions associated with serotonergic neurotransmitters. Therefore, the objective was to evaluate whether the association of serotonin (5-hydroxytryptamine, 5-HT) and ergot alkaloids during a 24 h pre-incubation could affect the vascular contractile response to ergot alkaloids. To evaluate the effects of 24 h exposure to 5-HT and ergot alkaloids (ergovaline, ERV), two assays were conducted. The first assay determined the half-maximal inhibitory concentration (IC50) following the 24 h pre-exposure period, while the second assay evaluated the effect of IC50 concentrations of 5-HT and ERV either individually or in combination. There was an interaction between previous exposure to 5-HT and ERV. Previous exposure to 5-HT at the IC50 concentration of 7.57 × 10−7 M reduced the contractile response by more than 50% of control, while the exposure to ERV at IC50 dose of 1.57 × 10−10 M tended to decrease (p = 0.081) vessel contractility with a response higher than 50% of control. The 24 h previous exposure to both 5-HT and ERV did not potentiate the inhibitory response of blood vessels in comparison with incubation with each compound alone. These results suggest receptor competition between 5-HT and ERV. More studies are necessary to determine the potential of 5-HT to treat toxicosis caused by ergot alkaloids.

Effect of Box Breathing Technique on Lung Function Test

Background: Box breathing exercise is a technique of slow breathing rhythm also known as square breathing used universally. It increases the performance and concentration level, it also acts as a powerful stress relief. It is tested with a spirometer for the lung function test that measures the airflow of the upper and lower respiratory tract. This method builds up carbon dioxide in blood which calms down and regulates the ANS (Autonomic Nervous System), which enhances the cardio- inhibitory response of the vagus nerve that improves the mood. The main aim of the study was to analyze the effect of box breathing technique on lung function Materials and Methods: The present study was carried out among the participants at the age of 18-25 years from Saveetha Dental College. A total of 30 participants were included in this study (15 males, 15 females). The experimental training procedures consisted of 2 sessions of box breathing day and night for a period of 30 days. Participants were informed of the procedures of the box breathing technique. RMS Helios spirometer was used to measure lung volumes and capacities. Statistics analysis was done using SPSS software, paired t test. P value of less than or equal to 0.05 was considered significant statistically. Results: There was a significant increase among the participants FVC (Forced Vital Capacity), FEV1 (Forced Expiratory Volume), FIVC (Forced Inspiratory Vital Capacity) parameters after 2 sessions on each day of box breathing technique for a period of 30 days. Other parameters increased to 10% but not significantly. Conclusion: The present study illustrates the potential for box breathing practice to improve lung performance and reduce stress in healthy individuals. Despite the significant difference in FVC, FEV, FIVC levels supporting improved lung function, further investigation is needed to delineate mechanisms that underlie these benefits

Predicting High-Risk Behaviors Based on Time Perspective in Iranian Adolescents by Emphasizing the Mediating Role of Decision Making and Inhibitory Response: Path Analysis

Background: Adolescence is defined as a period with multiple and intertwined physical, psychological, and social developments during which risky behaviors increases. Various factors affect the tendency and occurrence of risky behaviors. Time perspective (TP) is defined as the role of time and attitude toward time in affairs and behaviors. Executive functioning skills allow an individual to perceive stimuli from his or her environment, respond adaptively, flexibly change direction, anticipate future goals, consider consequences, and respond in an integrated or commonsense way. Objectives: This study aimed to predict risky behaviors based on TP in Iranian adolescents by emphasizing the mediating role of decision making and inhibitory response. Patients and Methods: Path analysis was used to evaluate the relationship between components of TP and risky behaviors with mediator variables, decision making, and inhibitory response among 804 high school adolescent students (including 470 males and 334 females) in Sanandaj, Iran. All participants were asked to complete the Iranian Adolescent Risk Scale and Time Perspective Scale and perform 2 computer tasks [i.e., Go/No-Go and Balloon Analogue Risk Task (BART)]. SPSS version 26 and AMOS version 24 were used to analyze direct and indirect relationships. Results: There was a significant relationship between the components of TP and the tendency to risky behaviors. Risky decision-making and inhibitory response had a significant effect on 3 aspects of TP in predicting adolescents’ risky behaviors. These effects were both direct and indirect, of which the former effect was created by mediating the decision-making and inhibitory response. Conclusions: The components of TP, decision-making, and inhibitory response predict risky behaviors in adolescents.

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored.

Complementary mechanisms of modulation of spontaneous phasic contractions by the gaseous signalling molecules NO, H2S, HNO and the polysulfide Na2S3 in the rat colon

Objectives Reactive oxygen and nitrogen species may be produced during inflammation leading to the formation of NO, H2S or HNO. Enzymes such as iNOS, CSE and CBS might also be responsible for polysulfide production. Since these signalling molecules might have an impact on colonic motility, the aim of this study was to compare their effect on rat colonic slow phasic contractions (SPC). Methods Organ bath measurements with strips obtained from rat proximal colon were performed using the polysulfide Na2S3, sodium nitroprusside (NaNP), sodium hydrogen sulfide (NaHS), Angeli’s salt as NO, H2S, and HNO donors, respectively. TTX (1 µM) was used to block neuronal activity. Results All four molecules, concentration-dependently, inhibited the amplitude and frequency of SPC both in the circular and longitudinal muscle layer. The relative potency was NaNP>Angeli’s salt>NaHS>Na2S3. The inhibitory response induced by NaNP (1 µM) and Angeli’s salt (50 µM) was reversed by ODQ (10 µM) whereas the inhibitory effect of NaHS (1 mM) was reversed by apamin (1 µM) and glibenclamide (10 µM). Na2S3 (1 mM) response was partially reversed by apamin (1 µM) and glibenclamide (10 µM). High concentrations of Na2S3 caused an increase in tone. Low concentrations of NaHS or Na2S3 did not potentiate NaNP responses. Conclusions All signalling molecules inhibit SPC in both muscle layers. The effect is independent of neural activity and involves guanylyl cyclase (NO and HNO) and SKCa and KATP channels (NaHS or Na2S3). Other pathways might also be involved in Na2S3 responses. Accordingly, complementary mechanisms of inhibition might be attributable to these signalling molecules.

AgRP neurons coordinate the mitigation of activity-based anorexia

Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented body weight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Moreover, while exercise has been shown to diminish the activity of hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons, much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals revealed a maladaptive inhibitory response to food. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.

Effectiveness of Interpersonal and Social Rhythm Therapy (IPSRT) With and Without Computer-based Cognitive Rehabilitation Therapy (CRT) in Promoting Emotion Dysregulation and Response Inhibition in Methamphetamine Abusers

Background: Despite extensive evidence on cognitive deficits and difficulty in emotion regulation related to substance abuse, especially methamphetamine abuse, a few well-organized programs could have improved cognitive abilities and emotion regulation in drug users. Objectives: The present study aimed to investigate the effectiveness of Interpersonal and Social Rhythm therapy (IPSRT) alone and combined with Cognitive Rehabilitation therapy (CRT) on inhibitory response and emotion dysregulation in people with methamphetamine use disorder. Patients and Methods: The current quasi-experimental study with a pretest-posttest and follow-up design included two intervention groups. Forty methamphetamine abusers were selected based on the inclusion and exclusion criteria and assigned randomly to the IPSRT (n = 20) and IPSRT + CRT (n = 20) groups. The first group received IPSRT in 12 sessions, two 60 min sessions per week. The second group received IPSRT and 16 sessions of CRT. Subjects were assessed three times at pre-intervention, immediately after the intervention, and four weeks after the intervention. Results: Data analyzed by descriptive statistics and mixed repeated ANOVA indicated that the two interventions had significant long-term effects on increasing the inhibitory response and decreasing emotion dysregulation. In addition, IPSRT with CRT was more effective than IPSRT alone in promoting executive functions and decreasing emotion dysregulation. Conclusions: The findings of this study provide evidence that adding CRT as an adjunct intervention to psychological interventions such as IPSRT can improve emotional and cognitive performance. Therefore, a combination of psychological interventions with CRT can be considered a useful intervention in addiction treatment centers.

Screening Youth Soccer Players by Means of Cognitive Function and Agility Testing

Talent identification in sports is a heavily debated topic. Previous studies have separately explored either executive functions or gross motor skills to predict the success of top-level soccer players or, more generally, to characterize elite performance in soccer. However, at mid-childhood, the possibility to scope sport-specific requirements remains elusive. We aimed in this study to investigate a valid and simple method of testing for a unique combination of cognitive and speed abilities for identifying promising soccer players at mid-childhood. We measured cognitive functions by means of a Stroop smartphone application and agility with a T-Drill Ball-success test, in two groups of (a) elite- ( n = 31) and (b) low-division ( n = 37) Italian 7-year-old male soccer players. We administered the tests in a randomized order to both groups. We found better inhibitory control, cognitive flexibility and soccer-specific agility in high-division versus low-division players ( p < .001). Inhibitory response and agility were positively associated with the augmented quality of the performance from low-division players to high-division players ( r = .55; p = .0001). These results suggest that, even at an early age, cognitive control together with soccer-specific skills is associated with better performance.

Plant-Based Synthesis of Zinc Oxide Nanoparticles (ZnO-NPs) Using Aqueous Leaf Extract of Aquilegia pubiflora: Their Antiproliferative Activity against HepG2 Cells Inducing Reactive Oxygen Species and Other In Vitro Properties

The anti-cancer, anti-aging, anti-inflammatory, antioxidant, and anti-diabetic effects of zinc oxide nanoparticles (ZnO-NPs) produced from aqueous leaf extract of Aquilegia pubiflora were evaluated in this study. Several methods were used to characterize ZnO-NPs, including SEM, FTIR, XRD, DLS, PL, Raman, and HPLC. The nanoparticles that had a size of 34.23 nm as well as a strong aqueous dispersion potential were highly pure, spherical or elliptical in form, and had a mean size of 34.23 nm. According to FTIR and HPLC studies, the flavonoids and hydroxycinnamic acid derivatives were successfully capped. Synthesized ZnO-NPs in water have a zeta potential of -18.4 mV, showing that they are stable solutions. The ZnO-NPs proved to be highly toxic for the HepG2 cell line and showed a reduced cell viability of 23.68 ± 2.1 % after 24 hours of ZnO-NP treatment. ZnO-NPs also showed excellent inhibitory potential against the enzymes acetylcholinesterase (IC50: 102 μg/mL) and butyrylcholinesterase (IC50: 125 μg/mL) which are involved in Alzheimer’s disease. Overall, the enzymes involved in aging, diabetes, and inflammation showed a moderate inhibitory response to ZnO-NPs. Given these findings, these biosynthesized ZnO-NPs could be a good option for the cure of deadly diseases such as cancer, diabetes, Alzheimer’s, and other inflammatory diseases due to their strong anticancer potential and efficient antioxidant properties.

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes.