Activity of selected aromatic amino acids in biological systems

Besides the structural function in proteins, aromatic amino acids are precursors of many important biological compounds essential for normal functioning of the human organism. Many of these compounds may be used as markers for identification of specific pathological states. Comprehensive knowledge about the metabolism of aromatic amino acids and mechanisms of action of their metabolites made it possible to develop effective treatments for many disorders. However, it should not be forgotten that in some pathological conditions, these compounds could not only be involved in the pathogenesis of many disease entities but could also be used as an important tool in prediction of many diseases. This paper contains a review of published literature on aromatic amino acids in the context of physiological processes of the human body and chosen social disorders, such as cancers; psychiatric disorders: depression, anxiety states, schizophrenia, bipolar affective disorders; neurodegenerative, and cardiovascular diseases; chronic kidney insufficiency or diabetes

Ala54Thr Fatty Acid-Binding Protein 2 (FABP2) Polymorphism in Recurrent Depression: Associations with Fatty Acid Concentrations and Waist Circumference

BACKGROUND: Fatty acid (FA)-alterations may mediate the mutual association between Major Depressive Disorder (MDD) and cardiovascular disease (CVD). However, etiology of observed FA-alterations in MDD and CVD remains largely unclear. An interesting candidate may be a mutation in the fatty acid-binding protein 2 (FABP2)-gene, because it regulates dietary FA-uptake. Therefore, we aimed to test the hypotheses that in MDD-patients the FABP2 Ala54Thr-polymorphism would be (I) more prevalent than in sex- and age-matched controls, (II) associated with observed alterations in FA-metabolism, and (III) associated with CVD-risk factor waist circumference. METHODS: We measured concentrations of 29 different erythrocyte FAs, FABP2-genotype, and waist circumference in recurrent MDD-patients and matched never-depressed controls. RESULTS: FABP2-genotype distribution did not significantly differ between the 137 MDD-patients and 73 matched controls. However, patients with the Ala54Thr-polymorphism had (I) higher concentrations of especially eicosadienoic acid (C20:2ω6; P=.009) and other 20-carbon FAs, and associated (II) lower waist circumference (P=.019). In addition, FABP2-genotype effects on waist circumference in patients seemed (I) mediated by its effect on C20:2ω6, and (II) different from controls. CONCLUSIONS: Although Ala54Thr-polymorphism distribution was not associated with recurrent MDD, our results indicate that FABP2 may play a role in the explanation of observed FA-alterations in MDD. For Ala54Thr-polymorphism patients, potentially adaptive conversion of increased bioavailable dietary precursors into eicosadienoic acid instead of arachidonic acid might be related to a low waist circumference. Because this is the first investigation of these associations, replication is warranted, preferably by nutrigenetic studies applying lipidomics and detailed dietary assessment

Exploring metabolic dysfunction in chronic kidney disease

Abstract Impaired kidney function and chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and −6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS), with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid receptor. Insight into the multiple factors altered in CKD may provide useful information on disease pathogenesis, clinical assessment and treatment rationale such as potential pharmacological, nutritional and exercise therapies

Poststroke Depression as a Factor Adversely Affecting the Level of Oxidative Damage to Plasma Proteins during a Brain Stroke

Poststroke depression, the second most serious psychosomatic complication after brain stroke, leads to delay of the rehabilitation process and is associated with an increased disability and cognitive impairment along with increase in termmortality. Research into the biochemical changes in depression is still insufficiently described. The aim of our study was therefore to evaluate the possible association between plasma protein oxidative/nitrative damages and the development of poststroke depression. We evaluated oxidative/nitrative modifications of specific proteins by measurement of 3-nitrotyrosine and carbonyl groups levels using ELISA test. Additionally, we checked differences in proteins thiol groups by spectrophotometric assay based on reaction between DTNB and thiols. We also evaluated catalase activity in erythrocytes measured as ability to decompose H2O2. Correlation analysis was performed using Spearman’s rank. We observed significant ( < 0.001) differences in all oxidative/nitrative stress parameters in brain stroke patients compared to healthy group.Our research shows that oxidative damage of proteins is correlated with the degree of poststroke depression, while nitrative changes do not show any relationship.We demonstrate a positive correlation between the concentration of carbonyl groups and the Geriatric Depression Scale and a negative correlation between the degree of depression and the concentration of -SH groups or catalase activity

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p&lt;0.0005, q&lt;0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p&lt;0.0001, q&lt;0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p&lt;0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p&lt;0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug

Understanding the gastrointestinal tract of the elderly to develop dietary solutions that prevent malnutrition

Although the prevalence of malnutrition in the old age is increasing worldwide a synthetic understanding of the impact of aging on the intake, digestion, and absorption of nutrients is still lacking. This review article aims at filling the gap in knowledge between the functional decline of the aging gastrointestinal tract (GIT) and the consequences of malnutrition on the health status of elderly. Changes in the aging GIT include the mechanical disintegration of food, gastrointestinal motor function, food transit, chemical food digestion, and functionality of the intestinal wall. These alterations progressively decrease the ability of the GIT to provide the aging organism with adequate levels of nutrients, what contributes to the development of malnutrition. Malnutrition, in turn, increases the risks for the development of a range of pathologies associated with most organ systems, in particular the nervous-, muscoskeletal-, cardiovascular-, immune-, and skin systems. In addition to psychological, economics, and societal factors, dietary solutions preventing malnutrition should thus propose dietary guidelines and food products that integrate knowledge on the functionality of the aging GIT and the nutritional status of the elderly. Achieving this goal will request the identification, validation, and correlative analysis of biomarkers of food intake, nutrient bioavailability, and malnutrition.info:eu-repo/semantics/publishedVersio

Targeting brain, body and heart for cognitive health and dementia prevention

This report looks into the current research regarding dementia and&nbsp;Alzheimer\u27s disease prevention and offers ideas for possible future solutions.&nbsp;Prevention of dementia is the ultimate aim of a large, albeit under resourced, international research effort. The success of this effort would have enormous benefits for millions of people and save billions of dollars in health care costs. Conversely, the status quo will see the number of Australians living with dementia soar in coming years. Many more people will experience and seek help for mild cognitive impairment. There are many different forms of dementia, a syndrome caused by brain disease and characterised by declining cognitive function that impairs daily activities. Dementia can affect memory, language, attention, judgement, planning, behaviour, mood and personality. Mild cognitive impairment does not significantly impair daily activities, but often represents an earlier stage of cognitive decline. There is no cure for the common forms of cognitive decline and dementia, including the most common, Alzheimer’s disease. A cure may only be achieved by prevention, because the diseases that cause dementia begin many years before symptoms become apparent and gradually damage the brain until it can no longer function normally. Intervening early to stop or slow disease progression, before cognitive impairment emerges, offers the best hope of preventing dementia. Is this achievable? It requires breakthroughs in early detection and intervention. New diagnostic technologies have been developed that can detect the presence of abnormal protein accumulations in the brain that characterise Alzheimer’s disease. The disease can now be detected by brain scans or cerebrospinal fluid tests in the preclinical stage, before any cognitive changes occur

Site-Directed Mutagenesis and Site-Specific Binding Analysis of Calmodulin (CaM)

Calcium signaling is a major regulatory system in cells and a crucial part of cell biology. An important element in the decoding of intracellular calcium concentration into downstream processes is the ubiquitous and highly conserved calcium binding protein calmodulin (CaM) which can bind to and modulate the function of hundreds of different target proteins, regulating such processes as synaptic plasticity, gene expression and electrical signaling. The biophysical characterization of binding affinity and cooperative interactions between each of calmodulin’s four EF-hand calcium binding sites is essential for understanding calcium signaling. Highly conserved amino acid sequence differences in the ion binding loops of the EF-hands give each site unique affinity for calcium. EF-hands are almost always found in pairs, where binding to one of the sites affects the affinity of the paired site. We have used spectroscopy to measure site-specific binding in each of the paired binding sites in the CaM N-lobe, along with site-directed mutagenesis, to study the contributions of individual amino acids to the ion binding affinity in the mutated site (cis effects) and in the neighboring site (trans effects). Of the twelve amino acids in the binding loops, five are different between Site 1 and Site 2. We constructed proteins with substituted individual residues from Site 1 to Site 2. CaM with the full Site 1 sequence in both Site 1 and Site 2 shows significant changes in affinity and binding characteristics in both sites. To investigate the contributions of the individual amino acid differences, we made intermediate mutants containing individual amino acid changes in Site 2. The cis-effects of the intermediate mutations on the mutated site, Site 2, seem to be independent and additive, whereas the trans-effects on the non-mutated Site 1 showed unexpected dependence on combinations of amino acid changes in Site 2.Neuroscienc

What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4’s role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging

Raja Bandung Banana (Musa ParadisiacaL.cv Raja Bandung) Prevents Increased Systolic Blood Pressure in Rats Given Acute Stress Test

The relationships between stress and hypertension have been evaluated. Heightened blood pressure (BP) reactions to acute stress have been implicated in cardiovascular disease\u27s development. Consumption of fruit or vegetables lowering BP. This study aimed to evaluate the effect of Raja Bandung Banana (Musa paradisiacaL. cv Raja Bandung) on blood pressure after acute restraint stress and forced swim test.Twenty male Sprague dawley rats were divided into 4 groups (A,B,C,D) and adapted for 3 days. At 4th day, groups were administered 2 g/200gBw AIN-93M, then exposed to acute restraint (1hour), except group A. After restraint, A&amp;B received water, C received diazepam 0,5mg/kgBW, and D received banana 2,52 g/200gBW. One hour later, the forced swim test was carried out (45 minutes). Blood pressure was measured 1 hour after swim. Result showed,mean of blood pressure significantly increased after treatment (p&lt;0,01) all groups. But, the increasing of blood pressure in C and D group was lower than unrestraint (A) and control (B) group. There was significant difference of blood pressure between control (A&amp;B) and intervention group (C&amp;D), but no significant difference between C and D. Thisresults indicate that Raja Bandung Banana can prevent increased blood pressure on acute stress condition as effective as diazepam