Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases.

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 taste of neuroinflammation: Molecular mechanisms linking taste sensing to neuroinflammatory responses.

Evidence indicates a critical role of neuroinflammatory response as an underlying pathophysiological process in several central nervous system disorders, including neurodegenerative diseases. However, the molecular mechanisms that trigger neuroinflammatory processes are not fully known. The discovery of bitter taste receptors in regions other than the oral cavity substantially increased research interests on their functional roles in extra-oral tissues. It is now widely accepted that bitter taste receptors, for instance, in the respiratory, intestinal, reproductive and urinary tracts, are crucial not only for sensing poisonous substances, but also, act as immune sentinels, mobilizing defense mechanisms against pathogenic aggression. The relatively recent discovery of bitter taste receptors in the brain has intensified research investigation on the functional implication of cerebral bitter taste receptor expression. Very recent data suggest that responses of bitter taste receptors to neurotoxins and microbial molecules, under normal condition, are necessary to prevent neuroinflammatory reactions. Furthermore, emerging data have revealed that downregulation of key components of the taste receptor signaling cascade leads to increased oxidative stress and inflammasome signaling in neurons that ultimately culminate in neuroinflammation. Nevertheless, the mechanisms that link taste receptor mediated surveillance of the extracellular milieu to neuroinflammatory responses are not completely understood. This review integrates new data on the molecular mechanisms that link bitter taste receptor sensing to neuroinflammatory responses. The role of bitter taste receptor-mediated sensing of toxigenic substances in brain disorders is also discussed. The therapeutic significance of targeting these receptors for potential treatment of neurodegenerative diseases is also highlighted.

Neuropathophysiology of coronavirus disease 2019: neuroinflammation and blood brain barrier disruption are critical pathophysiological processes that contribute to the clinical symptoms of SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is caused by the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) first discovered in Wuhan, Hubei province, China in December 2019. SARS-CoV-2 has infected several millions of people, resulting in a huge socioeconomic cost and over 2.5 million deaths worldwide. Though the pathogenesis of COVID-19 is not fully understood, data have consistently shown that SARS-CoV-2 mainly affects the respiratory and gastrointestinal tracts. Nevertheless, accumulating evidence has implicated the central nervous system in the pathogenesis of SARS-CoV-2 infection. Unfortunately, however, the mechanisms of SARS-CoV-2 induced impairment of the central nervous system are not completely known. Here, we review the literature on possible neuropathogenic mechanisms of SARS-CoV-2 induced cerebral damage. The results suggest that downregulation of angiotensin converting enzyme 2 (ACE2) with increased activity of the transmembrane protease serine 2 (TMPRSS2) and cathepsin L in SARS-CoV-2 neuroinvasion may result in upregulation of proinflammatory mediators and reactive species that trigger neuroinflammatory response and blood brain barrier disruption. Furthermore, dysregulation of hormone and neurotransmitter signalling may constitute a fundamental mechanism involved in the neuropathogenic sequelae of SARS-CoV-2 infection. The viral RNA or antigenic peptides also activate or interact with molecular signalling pathways mediated by pattern recognition receptors (e.g., toll-like receptors), nuclear factor kappa B, Janus kinase/signal transducer and activator of transcription, complement cascades, and cell suicide molecules. Potential molecular targets and therapeutics of SARS-CoV-2 induced neurologic damage are also discussed.

Stress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways.

Stress is a nonspecific response to a threat or noxious stimuli with resultant damaging consequences. Stress is believed to be an underlying process that can trigger central nervous system disorders such as depression, anxiety, and post-traumatic stress disorder. Though the pathophysiological basis is not completely understood, data have consistently shown a pivotal role of inflammatory mediators and hypothalamo-pituitary-adrenal (HPA) axis activation in stress induced disorders. Indeed emerging experimental evidences indicate a concurrent activation of inflammatory signaling pathways and not only the HPA axis, but also, peripheral and central renin-angiotensin system (RAS). Furthermore, recent experimental data indicate that the HPA and RAS are coupled to the signaling of a range of central neuro-transmitter, -mediator and -peptide molecules that are also regulated, at least in part, by inflammatory signaling cascades and vice versa. More recently, experimental evidences suggest a critical role of stress in disruption of the blood brain barrier (BBB), a neurovascular unit that regulates the movement of substances and blood-borne immune cells into the brain parenchyma, and prevents peripheral injury to the brain substance. However, the mechanisms underlying stress-induced BBB disruption are not exactly known. In this review, we summarize studies conducted on the effects of stress on the BBB and integrate recent data that suggest possible molecular mechanisms and signaling pathways underlying stress-induced BBB disruption. Key molecular targets and pharmacological candidates for treatment of stress and related illnesses are also summarized.

Cellular mechanisms and molecular signaling pathways in stress-induced anxiety, depression, and blood-brain barrier inflammation and leakage.

Depression and anxiety are comorbid conditions in many neurological or psychopathological disorders. Stress is an underlying event that triggers development of anxiety and depressive-like behaviors. Recent experimental data indicate that anxiety and depressive-like behaviors occurring as a result of stressful situations can cause blood-brain barrier (BBB) dysfunction, which is characterized by inflammation and leakage. However, the underlying mechanisms are not completely understood. This paper sought to review recent experimental preclinical and clinical data that suggest possible molecular mechanisms involved in development of stress-induced anxiety and depression with associated BBB inflammation and leakage. Critical therapeutic targets and potential pharmacological candidates for treatment of stress-induced anxiety and depression with associated BBB dysfunctions are also discussed.

Role of the Autonomic Nervous System and Vascular Endothelial Factors in the Development of Primary Arterial Hypotension in Paediatric Patients.

BACKGROUND: There is a dearth and inconsistency of data on the role of the autonomic nervous system (ANS) in the development of arterial hypotension. Also, little is known about the involvement of endothelial factors in the development of this disease. The aim of the study was to investigate the role of the ANS and endothelial factors or vasoregulators in the development of primary arterial hypotension (PAH) in children. METHODS: The cardiointervalography and clino-orthostatic test results of 113 children with PAH were compared with 88 healthy children of comparable age (7-11 years). Serum endothelial factors (nitric oxide and endothelins) of all children were measured. RESULTS: The findings revealed that children with PAH had higher activity of the sympathetic (p<0.001) and parasympathetic (p<0.001) divisions of the ANS at the initial (resting) position of clino-orthostatic test. The activity of these divisions of the autonomic nervous system correlated with the activity of a cardiac pacemaker. The change of position from horizontal into vertical was accompanied by a rise only in sympathetic activity (p<0.001). However, there was a decline in the sympathetic nervous system (p<0.001) compared to the indices of the initial (resting) position registered in the tenth minute of the vertical position. The parasympathetic division of the ANS based on heart rate variability showed high activity in all positions of the clino-orthostatic test in the patients with PAH compared with healthy children. The activity of the parasympathetic nervous system was associated with increased synthesis of endothelial factors (nitric oxide and endothelins) in blood. CONCLUSIONS: The inadequate response of the autonomic nervous system to the clino-orthostatic test in children with PAH is associated with disorders of both divisions of the autonomic nervous system as well as vascular endothelial factors.

Prevalence of alcohol-related problems among the Slavs and Arabs in Belarus: a university survey.

BACKGROUND: Alcohol abuse is a major problem among students in Belarus. Alcohol-related problems might vary among students of different cultural backgrounds. OBJECTIVES: To examine the different patterns in alcohol use and related problems among students of different cultural groups--the Slavs and Arabs, in major Belarusian universities. METHODS: 1465 university students (1345 Slavs and 120 Arabs) from three major universities in Minsk, Belarus, were administered the Alcohol Use Disorders Identification Test, the Cut, Annoyed, Guilty and Eye questionnaire, and the Michigan Alcohol Screening Test, including other alcohol-related questions. RESULTS: Overall, 91.08% (n = 1225) Slavs and 60.83% (n = 73) Arabs were alcohol users. A total of 16.28% (n = 219) Slavs and 32.50% (n = 39) Arabs were identified as problem drinkers. Different patterns of alcohol use and related problems were characterized for the Slavs and Arabs. The level of alcohol-related problems was higher among the Arabs, compared to the Slavs. CONCLUSION: Significant differences in the pattern of alcohol use and related problems exist among the students of various cultural groups--the Slavs and Arabs in Minsk, Belarus. SCIENTIFIC SIGNIFICANCE: This is the first empirical study to investigate the prevalence of alcohol use and related problems among the Arab and Slav students in Belarus.

The bitterness of genitourinary infections: Properties, ligands of genitourinary bitter taste receptors and mechanisms linking taste sensing to inflammatory processes in the genitourinary tract.

BACKGROUND: Though, first identified in the gastrointestinal tract, bitter taste receptors are now believed to be ubiquitously expressed in several regions of the body, including the respiratory tract, where they play a critical role in sensing and clearance of excess metabolic substrates, toxins, debris, and pathogens. More recently, bitter taste receptor expression has been reported in cells, tissues and organs of the genitourinary (GU) system, suggesting that these receptors may play an integral role in mediating inflammatory responses to microbial aggression in the GU tract. However, the mechanisms, linking bitter taste receptor sensing with inflammatory responses are not exactly clear. Here, I review recent data on the properties and ligands of bitter taste receptors and suggest mechanisms of bitter taste receptor signaling in the GU tract, and the molecular pathways that link taste sensing to inflammatory responses in GU tract. METHOD: Computer-aided search was conducted in Scopus, PubMed, Web of Science and Google Scholar for relevant peer-reviewed articles published between 1990 and 2018, investigating the functional implication of bitter taste receptors in GU infections, using the following keywords: extra-oral bitter taste receptors, bitter taste receptors, GU bitter taste receptors, kidney OR renal OR ureteral OR urethral OR bladder OR detrusor smooth muscle OR testes OR spermatozoa OR prostate OR vaginal OR cervix OR ovarian OR endometrial OR myometrial OR placenta OR cutaneous bitter taste receptors. To identify research gaps on etiopathogenesis of GU infections/inflammation, additional search was conducted using the following keywords: GU inflammatory signaling, GU microbes, GU bacteria, GU virus, GU protozoa, GU microbial metabolites, and GU infection. The retrieved articles were filtered and further screened for relevance according to the aim of the study. A narrative review was performed for selected literatures. RESULTS: Bitter taste receptors of the GU tract may constitute essential components of the pathogenetic mechanisms of GU infections/inflammation that are activated by microbial components, known as quorum sensing signal molecules. Based on accumulating evidences, indicating that taste receptors may signal downstream to activate inflammatory cascades, in addition to the nitric oxide-induced microbicidal effects produced upon taste receptor activation, it is suggested that the anti-inflammatory activities of bitter taste receptor stimulation are mediated via pathways involving the nuclear factor κB by downstream signaling of the metabolic and stress sensors, adenosine monophosphate-activated protein kinase and nicotinamide adenine dinucleotide-dependent silent mating type information regulation 2 homolog 1 (sirtuin 1), resulting to the synthesis of anti-inflammatory cytokines/chemokines, and antimicrobial factors, which ultimately, under normal conditions, leads to the elimination of microbial aggression. CONCLUSIONS: GU bitter taste receptors may represent critical players in GU tract infections/inflammation. Bitter taste receptors may serve as important therapeutic target for treatment of a number of infectious diseases that affect the GU tract.

Gut Microbiota Disorder, Gut Epithelial and Blood-Brain Barrier Dysfunctions in Etiopathogenesis of Dementia: Molecular Mechanisms and Signaling Pathways.

Emerging evidences indicate a critical role of the gut microbiota in etiopathogenesis of dementia, a debilitating multifactorial disorder characterized by progressive deterioration of cognition and behavior that interferes with the social and professional functions of the sufferer. Available data suggest that gut microbiota disorder that triggers development of dementia is characterized by substantial reduction in specific species belonging to the Firmicutes and Bacteroidetes phyla and presence of pathogenic species, predominantly, pro-inflammatory bacteria of the Proteobacteria phylum. These changes in gut microbiota microecology promote the production of toxic metabolites and pro-inflammatory cytokines, and reduction in beneficial substances such as short chain fatty acids and other anti-inflammatory factors, thereby, enhancing destruction of the gut epithelial barrier with concomitant activation of local and distant immune cells as well as dysregulation of enteric neurons and glia. This subsequently leads to blood-brain barrier dysfunctions that trigger neuroinflammatory reactions and predisposes to apoptotic neuronal and glial cell death, particularly in the hippocampus and cerebral cortex, which underlie the development of dementia. However, the molecular switches that control these processes in the histo-hematic barriers of the gut and brain are not exactly known. This review integrates very recent data on the molecular mechanisms that link gut microbiota disorder to gut epithelial and blood-brain barrier dysfunctions, underlying the development of dementia. The signaling pathways that link gut microbiota disorder with impairment in cognition and behavior are also discussed. The review also highlights potential therapeutic options for dementia.

Current Perspectives and Mechanisms of Relationship between Intestinal Microbiota Dysfunction and Dementia: A Review.

BACKGROUND: Accumulating data suggest a crucial role of the intestinal microbiota in the development and progression of neurodegenerative diseases. More recently, emerging reports have revealed an association between intestinal microbiota dysfunctions and dementia, a debilitating multifactorial disorder, characterized by progressive deterioration of cognition and behavior that interferes with the social and professional life of the sufferer. However, the mechanisms of this association are not fully understood. SUMMARY: In this review, I discuss recent data that suggest mechanisms of cross-talk between intestinal microbiota dysfunction and the brain that underlie the development of dementia. Potential therapeutic options for dementia are also discussed. The pleiotropic signaling of the metabolic products of the intestinal microbiota together with their specific roles in the maintenance of both the intestinal and blood-brain barriers as well as regulation of local, distant, and circulating immunocytes, and enteric, visceral, and central neural functions are integral to a healthy gut and brain. KEY MESSAGES: Research investigating the effect of intestinal microbiota dysfunctions on brain health should focus on multiple interrelated systems involving local and central neuroendocrine, immunocyte, and neural signaling of microbial products and transmitters and neurohumoral cells that not only maintain intestinal, but also blood brain-barrier integrity. The change in intestinal microbiome/dysbiome repertoire is crucial to the development of dementia.

Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons.

The astrocyte-neuron lactate shunt (ANLS) hypothesis is the most widely accepted model of brain glucose metabolism. However, over the past decades, research has shown that neuronal and astrocyte plasma membrane receptors, in particular, GLUT2, Kir6.2 subunit of the potassium ATP-channel, SGLT-3 acting as glucosensors, play a pivotal role in brain glucose metabolism. Although both ANLS hypothesis and glucosensor model substantially improved our understanding of brain glucose metabolism, the latter appears to be gaining more attention in the scientific community as the former could not account for new research data indicating that hypothalamic and brainstem neurons may not require astrocyte-derived lactate for energy. More recently, emerging evidences suggest a crucial role of sweet taste receptors in brain glucose metabolism. Furthermore, a couple of intracellular molecules acting as glucosensors have been identified in central astrocytes and neurons. This review integrates new data on the mechanisms of brain glucose sensing and metabolism. The role of the glucosensors including the sweet taste T1R2 + T1R3-mediated brain glucose-sensing and metabolism in brain glucose metabolic disorders is discussed. Possible role of glucose sensors (GLUT2, K-ATPKir6.2, SGLT3, T1R2 + T1R3) in brain diseases involving metabolic dysfunctions and the therapeutic significance in targeting central glucosensors for the treatment of these brain diseases are also discussed.

A case study: Effects of foot reflexotherapy on ADHD symptoms and enuresis nocturia in a child with ADHD and enuresis nocturia.

BACKGROUND AND PURPOSE: Symptoms of Attention-Deficit Hyperactivity Disorder (ADHD) can occur in association with enuresis nocturia. Alternative therapies may be effective in addressing the maladies of children with ADHD comorbidities. The purpose of this study was to investigate the effects of foot reflexotherapy in a child with ADHD and enuresis nocturia. MATERIALS AND METHODS: The patient was an 8-year-old child with ADHD and enuresis nocturia. Pre- and post-tests for ADHD were completed using Vanderbilt ADHD Diagnostic Teacher Rating Scale. The subject was treated with foot reflexotherapy for 20-min per session twice per week for a period of 8 weeks. RESULTS: The child showed improvement in ADHD symptoms and his enuresis nocturia disappeared completely after foot reflexotherapy. CONCLUSION: Foot reflexotherapy was effective in improving inattention, hyperactivity in the child with ADHD. The results of this novel study suggest that foot reflexotherapy can be effective in treating ADHD child with enuresis nocturia.

The Effects of Wet Cupping Therapy on the Blood Levels of Some Heavy Metals: A Pilot Study.

BACKGROUND AND AIM: Heavy metals have been recognized as toxins for centuries. Cupping therapy has been shown to aid in the excretion of accumulated fluids and toxins from the interstitial fluid. The aim of this study was to investigate the effects of wet cupping therapy on blood levels of heavy metals. METHODS: Thirteen healthy male individuals [mean age ± standard deviation, 28.47 ± 6.18] participated in this study. Venous blood samples were collected 5 min before and 30 days after the wet cupping therapy. Five points of the posterior neck and bilateral perispinal areas of the neck and thoracic spine were selected for cupping therapy. The levels of aluminium (Al), zinc (Zn), and cadmium (Cd) were measured using an atomic absorption spectrophotometer. RESULTS: The levels of heavy metals (Al, Zn, and Cd) after cupping therapy were significantly lower than the levels before therapy. CONCLUSIONS: These results suggest that wet cupping therapy has an excretory effect on the kidney. Wet cupping therapy may clear blood from excess heavy metals.

The effect of foot reflexotherapy on the dynamics of cortical oscillatory waves in healthy humans: An EEG study.

BACKGROUND: Foot reflexotherapy is a noninvasive complementary therapy that has gained considerable application in several fields of human endeavor. The therapy is used to relieve the symptoms of several ailments. For instance, foot reflexotherapy when applied to the cortical areas of the left or right foot relieves pain and stress. However, the electrophysiological mechanisms of the effect of foot reflexotherapy on cortical activity are not completely understood. While it has been shown that foot reflexotherapy exert positive effects on brain functions, little is known about the effects of this therapy on cortical activities as recorded with electroencephalogram (EEG) in healthy humans. Cortical activity is widely investigated with EEG, a noninvasive recording that is used to study brain activity in different functional states and conditions. AIM: The aim of this study was to investigate the effect of foot reflexotherapy on EEG rhythms in healthy humans. MATERIAL AND METHODS: EEG recording before and after reflexological therapy was carried out in seven healthy right-handed males who volunteered for the study. RESULTS: Analysis of EEG data revealed activation offrontal cortex that resulted to significant increase in beta and gamma spectral powers after foot reflexotherapy (p ˂ 0.05). CONCLUSION: Foot reflexotherapy is associated with increase in spectral powers in beta and gamma frequency bands. Therefore cortical beta and gamma waves of the EEG could be used as measures of functional activation of the brain, related to foot reflexotherapy.

Sweet taste receptor signaling network: possible implication for cognitive functioning.

Sweet taste receptors are transmembrane protein network specialized in the transmission of information from special "sweet" molecules into the intracellular domain. These receptors can sense the taste of a range of molecules and transmit the information downstream to several acceptors, modulate cell specific functions and metabolism, and mediate cell-to-cell coupling through paracrine mechanism. Recent reports indicate that sweet taste receptors are widely distributed in the body and serves specific function relative to their localization. Due to their pleiotropic signaling properties and multisubstrate ligand affinity, sweet taste receptors are able to cooperatively bind multiple substances and mediate signaling by other receptors. Based on increasing evidence about the role of these receptors in the initiation and control of absorption and metabolism, and the pivotal role of metabolic (glucose) regulation in the central nervous system functioning, we propose a possible implication of sweet taste receptor signaling in modulating cognitive functioning.

Cognitive functions and neuropsychological status of medical students with different attitudes to alcohol use: a study conducted at the Belarusian State Medical University, Minsk, Belarus.

This article presents findings on the effects of alcohol use on cognitive performance, functional (well-being, activity, mood) and neuropsychological status and anxiety levels of medical students. A total of 265 medical students (107 males and 158 females) from the Belarusian State Medical University, Minsk (Belarus) were administered questionnaire, containing the AUDIT, CAGE, MAST, and PAS, and other alcohol related questions. Academic Performance questionnaire was administered together with other tests. For analysis of cognitive functions, a "correction probe" test was used. The number of students who reported consumption of alcohol was 74 males and 142 females. Medical students who reported alcohol consumption had lower cognitive performance and academic success, poor self-assessment of their functional and neuropsychological states, compared to the non-alcohol users. The results of this study suggest an inverse dose-dependent relationship between alcohol consumption, and cognitive functions, academic performance and neuropsychological status of medical students.