Pentylenetetrazole (PTZ), a tetrazole derivative, is commonly used as a chemical agent to induce neurological disorders and replicate the characteristics of human epileptic seizures in animal models. This review offers a comprehensive analysis of the behavioral, neurophysiological, and neurochemical changes induced by PTZ. The epileptogenic and neurotoxic mechanisms of PTZ are associated with an imbalance between the GABAergic and glutamatergic systems. At doses exceeding 60 mg/kg, PTZ exerts its epileptic effects by non-competitively antagonizing GABAA receptors and activating NMDA receptors, resulting in an increased influx of cations such as Na+ and Ca2+. Additionally, PTZ promotes oxidative stress, microglial activation, and the synthesis of pro-inflammatory mediators, all of which are features characteristic of glutamatergic excitotoxicity. These mechanisms ultimately lead to epileptic seizures and neuronal cell death, which depend on the dosage and method of administration. The behavioral, electroencephalographic, and histological changes associated with PTZ further establish it as a valuable preclinical model for the study of epileptic seizures, owing to its simplicity, cost-effectiveness, and reproducibility.

While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer's disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer's disease. This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer's Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.

Bitter taste receptors (TAS2Rs) and their downstream signaling pathways are expressed not only in the oral tissues but also in extraoral tissues. Emerging data has demonstrated the beneficial effect of ghrelin in neurodegenerative diseases. Gaining more insight into the interaction between TAS2Rs and gut hormones may expand their therapeutic applications. Herein, we aimed to assess the possible effect of TAS2R activation by denatonium benzoate (DB) in modulating functional and neurobiochemical alterations in a model of Parkinson's disease (PD).

PD model was induced by daily injection of rotenone (2 mg/kg). Rats received DB (5 mg/kg), atenolol (10 mg/kg), or both concomitantly with rotenone, daily for 28 days. Evaluation of the motor abnormalities and histological examination of brain tissues were conducted. In addition, striatal dopamine contents, immunohistochemical expression of tyrosine hydroxylase, plasma ghrelin level, and biochemical analysis of markers of inflammation and oxidative stress were assessed.

Treatment with DB increased serum levels of ghrelin and striatal dopamine contents with consequent amelioration of oxidative stress and attenuation of inflammatory cytokines. Moreover, DB treatment significantly ameliorated motor disturbance and histological abnormalities compared to untreated rats. Atenolol inhibited ghrelin release and abolished the positive effect of DB suggesting the involvement of ghrelin on such effects.

The current study suggests that TAS2Rs agonists are promising candidates for ameliorating rotenone-induced PD pathology in rats, an action that could be linked to the enhancement of ghrelin release with consequent antioxidant and anti-inflammatory activities.

While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer's disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer's disease.

This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer's Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel.

The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3.

Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.

Bitter taste receptors (TAS2Rs) are not only responsible for taste perception in the oral cavity, but are spread throughout the body, generating a widespread chemosensory system. In humans, 25 subtypes have been identified and are differentially expressed in tissues and organs, including in the immune system. In fact, several TAS2R subtypes have been detected in neutrophils, lymphocytes, B and T cells, NK cells, and monocytes/macrophages, in which they regulate various protective functions of the innate immune system. Given its recognized anti-inflammatory and antioxidant activity, and the generally protective role of bitter taste receptors, in this work, we studied TAS2R46's potential in the protection of human monocyte/macrophage DNA from stress-induced damage. Through both direct and indirect assays and a single-cell gel electrophoresis assay, we demonstrated that absinthin, a specific TAS2R46 agonist, counteracts the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and reduces DNA damage in both cell types. Even though the release of ROS from monocytes/macrophages is fundamental for contrast pathogen agents, supraphysiological ROS production impairs their function, finally leading to cell death. Our results highlight TAS2R46 as a novel player involved in the protection of monocytes and macrophages from oxidative stress damage, while simultaneously supporting their antimicrobial activity.

This study aimed to evaluate the spasmolytic activity of an underground parts extract of Gentiana asclepiadea L. (Gentianaceae), assess its antioxidant and antimicrobial activities, and explore the impact of extract encapsulation on the aforementioned bioactivities. An extract encapsulated by spray drying with whey protein, pure extract, and pure whey protein were comparatively tested. The main compounds identified via HPLC-DAD analysis underwent in silico ADME assessment. The spasmolytic effect was tested on a model of spontaneous rat ileum contractions, and the mechanism of action was further evaluated on acetylcholine-, KCl-, CaCl2-, BaCl2-, histamine-, N(ω)-nitro-L-arginine methyl ester-, and glibenclamide-modified contractions. The most abundant compounds were secoiridoids (dominantly gentiopicroside), followed by C-glycosylated flavonoids and xanthones. Both pure and encapsulated extracts achieved significant spasmolytic effects, despite the spasmogenic activity of pure whey protein. The extract may exert its spasmolytic effect through multiple pathways, predominantly by antagonizing the Ca2+ channel and opening the K+ channel, while the nitric oxide pathway appears not to be involved. The antimicrobial and antioxidant activities of the pure extract were moderate. The extract stabilized by encapsulation retained all of the tested bioactivities of the unencapsulated extract. The obtained results suggest that G. asclepiadea has potential for use in the treatment of some gastrointestinal complaints and that the encapsulated extract could be a valuable functional ingredient in pharmaceutical and food products.

Aspartame (APM) is one of the most widely used artificial sweeteners worldwide. Studies have revealed that consuming APM may negatively affect the body, causing oxidative stress damage to multiple organs and leading to various neurophysiological symptoms. However, it's still unclear if consuming APM and one's daily biological rhythm have an interactive effect on health. In this study, healthy adult C57BL/6 mice were randomly divided into four groups: Control group (CON), oral gavage sham group (OGS), daytime APM intragastric group (DAI) and nighttime APM intragastric group (NAI). DAI and NAI groups were given 80 mg/kg body weight daily for 4 weeks. We found that DAI and NAI groups had significantly increased mean body weight, higher serum corticosterone levels, up-regulated pro-inflammatory responses in serum and brain, and exacerbated depressive-like behaviors than the CON and the two APM intake groups. Moreover, all these changes induced by APM intake were more significant in the DAI group than in the NAI group. The present study, for the first time, revealed that the intake of APM and daily biological rhythm have an interactive effect on health. This suggests that more attention should be paid to the timing of APM intake in human beings, and this study also provides an intriguing clue to the circadian rhythms of experimental animals that researchers should consider more when conducting animal experiments.

The study aimed to investigate the association between the TAS2R16 gene (rs860170, rs978739, rs1357949), TAS2R16 serum levels, and multiple sclerosis (MS). A total of 265 healthy control subjects and 218 MS patients were included in the study. Single nucleotide polymorphisms (SNPs) were tested by real-time polymerase chain reaction (RT-PCR). The serum concentration of TAS2R16 was measured using the ELISA method. Analyses revealed that the TAS2R16 rs860170 TT genotype was statistically significantly less frequent in the MS group than in the control group (p = 0.041), and the CC genotype was statistically significantly more frequent in the MS group than in the control group (p < 0.001). In the most robust (codominant) model, the CC genotype was found to increase the odds of MS by ~27-fold (p = 0.002), and each C allele increased the odds of MS by 1.8-fold (p < 0.001). Haplotype analysis of the rs860170, rs978739, and rs1357949 polymorphisms showed that the C-C-A haplotype was associated with a ~12-fold increased odds of MS occurrence (p = 0.02). Serum TAS2R16 levels were elevated in the MS group compared to control subjects (p = 0.014). Conclusions: The rs860170, rs978739, and rs1357949 polymorphisms demonstrated that the C-C-A haplotype and elevated TAS2R16 serum levels can promote the development of MS. These preliminary findings underscore the importance of specific genetic variants, such as rs860170, rs978739, and rs1357949, in MS risk. Additionally, elevated TAS2R16 serum levels in MS patients suggest a potential role in MS pathogenesis. These findings provide insights into the genetic and molecular mechanisms underlying MS and pave the way for personalized diagnostic and therapeutic strategies. Integrating genetic and serum biomarker data in MS research offers promising avenues for improving clinical outcomes and advancing precision medicine approaches in the future.

Modulation of brain olfactory (OR) and taste receptor (TASR) expression was recently reported in neurological diseases. However, there is still limited evidence of these genes' expression in the human brain and the transcriptional regulation mechanisms involved remain elusive. We explored the possible expression and regulation of selected OR and TASR in the human orbitofrontal cortex (OFC) of sporadic Alzheimer's disease (AD) and non-demented control specimens using quantitative real-time RT-PCR and ELISA. Global H3K9me3 amounts were measured on OFC total histone extracts, and H3K9me3 binding at each chemoreceptor locus was examined through native chromatin immunoprecipitation. To investigate the potential interactome of the repressive histone mark H3K9me3 in OFC specimens, native nuclear complex co-immunoprecipitation (Co-IP) was combined with reverse phase-liquid chromatography coupled to mass spectrometry analysis. Interaction between H3K9me3 and MeCP2 was validated by reciprocal Co-IP, and global MeCP2 levels were quantitated. We found that OR and TAS2R genes are expressed and markedly downregulated in OFC at early stages of sporadic AD, preceding the progressive reduction in their protein levels and the appearance of AD-associated neuropathology. The expression pattern did not follow disease progression suggesting transcriptional regulation through epigenetic mechanisms. We discovered an increase of OFC global H3K9me3 levels and a substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages of AD, ultimately lost at advanced stages. We revealed the interaction between H3K9me3 and MeCP2 at early stages and found that MeCP2 protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R transcriptional regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.

Heart diseases and related complications constitute a leading cause of death and socioeconomic threat worldwide. Despite intense efforts and research on the pathogenetic mechanisms of these diseases, the underlying cellular and molecular mechanisms are yet to be completely understood. Several lines of evidence indicate a critical role of inflammatory and oxidative stress responses in the development and progression of heart diseases. Nevertheless, the molecular machinery that drives cardiac inflammation and oxidative stress is not completely known. Recent data suggest an important role of cardiac bitter taste receptors (TAS2Rs) in the pathogenetic mechanism of heart diseases. Independent groups of researchers have demonstrated a central role of TAS2Rs in mediating inflammatory, oxidative stress responses, autophagy, impulse generation/propagation and contractile activities in the heart, suggesting that dysfunctional TAS2R signalling may predispose to cardiac inflammatory and oxidative stress disorders, characterised by contractile dysfunction and arrhythmia. Moreover, cardiac TAS2Rs act as gateway surveillance units that monitor and detect toxigenic or pathogenic molecules, including microbial components, and initiate responses that ultimately culminate in protection of the host against the aggression. Unfortunately, however, the molecular mechanisms that link TAS2R sensing of the cardiac milieu to inflammatory and oxidative stress responses are not clearly known. Therefore, we sought to review the possible role of TAS2R signalling in the pathophysiology of cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Potential therapeutic significance of targeting TAS2R or its downstream signalling molecules in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction is also discussed.

The bitter taste is generally considered an undesirable sensory attribute. However, bitter-tasting compounds can significantly affect the overall flavor of many foods and beverages and endow them with various beneficial effects on human health. To better understand the relationship between chemical structure and bitterness, this paper has summarized the bitter compounds in foodstuffs and classified them based on the basic skeletons. Only those bitter compounds that are confirmed by human sensory evaluation have been included in this paper. To develop food products that satisfy consumer preferences, correctly ranking the key bitter compounds in foodstuffs according to their contributions to the overall bitterness intensity is the precondition. Generally, three methods were applied to screen out the key bitter compounds in foods and beverages and evaluate their sensory contributions, including dose-over-threshold factors, taste dilution analysis, and spectrum descriptive analysis method. This paper has discussed in detail the mechanisms and applications of these three methods. Typical procedures for separating and identifying the main bitter compounds in foodstuffs have also been summarized. Additionally, the activation of human bitter taste receptors (TAS2Rs) and the mechanisms of bitter taste transduction are outlined. Ultimately, a conclusion has been drawn to highlight the current problems and propose potential directions for further research.

The delivery of therapeutic drugs to the brain remains a major pharmacology challenge. A complex system of chemical surveillance to protect the brain from endogenous and exogenous toxicants at brain barriers hinders the uptake of many compounds with significant in vitro and ex vivo therapeutic properties. Despite the advances in the field in recent years, the components of this system are not completely understood. Recently, a large group of chemo-sensing receptors, have been identified in the blood-cerebrospinal fluid barrier. Among these chemo-sensing receptors, bitter taste receptors (TAS2R) hold promise as potential drug targets, as many TAS2R bind compounds with recognized neuroprotective activity (quercetin, resveratrol, among others). Whether activation of TAS2R by their ligands contributes to their diverse biological actions described in other cells and tissues is still debatable. In this review, we discuss the potential role of TAS2R gene family as the mediators of the biological activity of their ligands for the treatment of central nervous system disorders and discuss their potential to counteract drug resistance by improving drug delivery to the brain.