Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases and psychiatric disorders. The presence of positive feedback loops facilitates amplifying the immune responses vice versa.

Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1-3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with complex pathogenesis involving a variety of immunological events. Recently, it has been suggested that kynurenic acid (KYNA) might be a potential regulator of inflammatory processes in arthritis. KYNA has a definitive anti-inflammatory and immunosuppressive function.

The Opposite Effects of Kynurenic Acid and Different Kynurenic Acid Analogs on Tumor Necrosis Factor-α (TNF-α) Production and Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6) Expression.

The investigation of anti-inflammatory and immunosuppressive functions of Kynurenic acid (KYNA) is now in focus. There is also substantial evidence that TSG-6 has an anti-inflammatory activity. Therefore, in the present study, we compared the effects of newly synthetized KYNA analogs on the TNF-α production in U-937 monocytic cells in correlation with the effects on the TSG-6 expression.

Intraperitoneally administered IgG from patients with amyotrophic lateral sclerosis or from an immune-mediated goat model increase the levels of TNF-α, IL-6, and IL-10 in the spinal cord and serum of mice.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the selective loss of the upper and lower motor neurons (MNs). Neuroinflammation has been implicated in the pathogenesis of the sporadic form of the disease. We earlier developed immune-mediated animal models of ALS and demonstrated humoral and cellular immune reactions in the nervous system and in the sera of patients and animals.

Relevance of defensin β-2 and α defensins (HNP1-3) in Alzheimer's disease.

The DEFB4 gene copy numbers were investigated in 206 AD patients and in 250 controls. The levels of the human defensin β-2 (hBD2) and α-defensins (HNP 1-3) in the sera and in the cerebrospinal fluid (CSF) of the patients and the controls were determined. Higher copy numbers of the DEFB4 gene was observed in AD patients as compared with the controls.

Decreased Number of Mitochondria in Leukoaraiosis.

Background And Aims: Leukoaraiosis (LA), one of the most frequent causes of an age-associated cognitive decline, can be associated with a poor quality of life, leading overall to far-reaching public health problems. Chronic hypoxia of the white matter of the brain may be a factor triggering this entity. LA may develop as a consequence of chronically insufficient cellular energy production and the accumulation of free radicals.

GENETIC POLYMORPHISMS OF HUMAN β-DEFENSINS IN PATIENTS WITH MULTIPLE SCLEROSIS.

Aims: Recent studies have started to elucidate the contribution of microbiome to the pathogenesis of multiple sclerosis (MS). It is also supposed, that neuropathological alterations might be associated with abnormal expression and regulatory function of antimicrobial peptides (AMPs), including defensins. It is in our interest to investigate the relevance of the single nucleotide polymorphisms (SNPs) of the DEFB1 gene and the copy number polymorphism of the DEFB4 genes in MS.

Relevance of α-defensins (HNP1-3) and defensin β-1 in diabetes.

Aim: To investigate the genetic background of human defensin expression in type 1 and 2 diabetes.

Methods: Associations between DEFA1/DEFA3 gene copy number polymorphism and diabetes as well as between the promoter polymorphisms of DEFB1 and diabetes were studied. The copy number variation of the DEFA1/DEFA3 genes was determined in 257 diabetic patients (117 patients with type 1 and 140 with type 2 diabetes).

Induction of human defensins by intestinal Caco-2 cells after interactions with opportunistic Candida species.

In this study we investigated the effects of Candida albicans, Candida krusei, Candida tropicalis and Candida parapsilosis on human beta-defensin 2 (HBD-2) production in Caco-2 intestinal cell line, and the production of alpha-defensins (human neutrophil peptides, HNP 1-3) in peripheral blood. Opportunistic pathogen yeasts can modulate the host immune function by inducing defensins, the natural antimicrobial peptides. Here we show that Candida spp.

Evaluation of the MTHFR A1298C variant in leukoaraiosis.

Vascular demyelinization of the white matter of the brain is referred to as leukoaraiosis (LA). This very frequent entity is associated with a cognitive decline, thereby resulting in a deteriorating quality of life. Besides poorly controlled hypertension and aging, its development is reported to be associated with an elevated serum homocysteine level.

The kynurenine system and immunoregulation.

There is developing interest in the role of the kynurenines in the immune function. A considerable amount of evidence has accumulated as concerns interactions between the kynurenine pathway, cytokines and the nervous system. Indoleamine 2,3-dioxygenase (IDO) occupies a key position connecting the immune system and the kynurenine pathway.

Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-α (TNF-α) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils.

Kynurenic acid (KynA), a broad spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The potential anti-inflammatory effect of KynA in human leukocytes has not been characterized. The aim of this study was to compare the effects of KynA with those of a new analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride on tumour necrosis factor-α (TNF-α) production and high mobility group box protein 1 (HMGB1) secretion.

Inducible expression of human β-defensin 2 by Chlamydophila pneumoniae in brain capillary endothelial cells.

Defensins are an important family of natural antimicrobial peptides. Chlamydophila pneumoniae, a common cause of acute respiratory infection, has a tendency to cause persistent inflammatory diseases such as atherosclerosis, which may lead to cardiovascular disease or stroke. As endothelial cells are related to the physiopathology of stroke, the effects of in vitro C.

Involvement of p63 in the herpes simplex virus-1-induced demise of corneal cells.

Background: The transcription factor p63 plays a pivotal role in the development and maintenance of epithelial tissues, including the ocular surface. In an effort to gain insight into the pathogenesis of keratitis caused by HSV-1, we determined the expression patterns of the p63 and Bax proteins in the Staatens Seruminstitute Rabbit Cornea cell line (SIRC).

Methods: SIRC cells were infected with HSV-1 at various multiplicities and maintained for different periods of time.

RAGE gene polymorphisms in patients with multiple sclerosis.

The pathogenesis of multiple sclerosis (MS), a devastating neuroinflammatory disorder of the central nervous system, has been presumed to involve the possible importance of the receptor for advanced glycation end products (RAGE). The aim of this study was to investigate the relevance of the genetic polymorphisms of RAGE in MS patients. A total of 168 patients with MS were enrolled; 136 healthy blood donors served as controls.

Evaluation of the genetic variants of kinesin motor protein in ischemic stroke.

Background: The kinesin light-chain 1 genetic variants G56836C, A185C, and C406T were earlier found to amplify the development of leukoaraiosis in hypertensive smokers. These 3 variants were presumed to affect the function of the mitochondria, thereby giving rise to sensitivity to a chronic ischemic state. We have now extended our investigations to examine how the above genetic variants affect the occurrence of ischemic stroke.

A homozygous genetic variant of mitochondrial uncoupling protein 4 exerts protection against the occurrence of multiple sclerosis.

Multiple sclerosis (MS), which results in damage of the white matter at multiple foci, poses a far-reaching public health problem in view of the burden it imposes on the affected young and middle-aged. Some previous data suggested that roles could be played in the demyelinization of the white matter of the brain by the malfunctioning of the mitochondria and mitochondria-associated reactive oxygen species. In this context, we hypothesized that the finely tuned dynamic stability of the mitochondrial membrane potential (MMP), which is the main mirror of the functional state of the mitochondria, is essential for the intact nature of the glia cells in the brain.

The herpes simplex virus-induced demise of keratinocytes is associated with a dysregulated pattern of p63 expression.

p63 plays a pivotal role in the development and maintenance of stratified epithelial tissues. In an effort to gain insight into the pathogenic mechanisms of skin infections caused by HSV-1 and HSV-2, we determined the patterns of p63 expression in primary keratinocytes and in the HaCaT cell line. The levels of DeltaNp63alpha and a 50kDa p73 isoform were decreased, Bax-alpha remained unaffected, while the expressions of the Bax-beta, TAp63gamma and a 44.

Gene-environmental effects behind leukoaraiosis: a silent genetic variant of the kinesin protein can be activated in a subject with poorly controlled long-lasting hypertension.

Objectives: The rs8702 variant of the kinesin light chain 1 was earlier found to be a risk factor for vascular white matter demyelinization, referred to as leukoaraiosis (LA), in hypertensive smokers. The aim of this study was to determine the extent to which this genetic variant gives rise to the occurrence of LA and its severity, if the subject is exposed to long-lasting, severe and poorly controlled hypertension.

Design And Methods: The clinical and genetic data on 204 LA patients without infarction and 240 neuroimaging alteration-free subjects were analyzed.

Potential role of human beta-defensin 1 in Helicobacter pylori-induced gastritis.

Objective: Helicobacter pylori-induced gastric inflammation is dependent on the persistence of the microorganism in the gastric epithelium. Modulation of the host epithelial antimicrobial responses may be a critical determinant in H. pylori-induced gastritis.

Association of beta-defensin 1 single nucleotide polymorphisms with Crohn's disease.

Objective: It has been suggested that deficient defensin expression is associated with the chronic inflammation of Crohn's disease. The regional localization of Crohn's disease, ileal or colonic disease can be linked to different defensin profiles. As constitutive beta-defensin 1 has a colonic expression, we considered it of interest to investigate single nucleotide polymorphisms (SNPs) of the beta-defensin 1 gene (DEFB1) in Crohn's disease.

Characteristic imprint of single nucleotide polymorphisms in multiple sclerosis.

Although the main pathomechanism of multiple sclerosis (MS) is not known, an autoimmune response against the myelin basic proteins (MBPs) is presumed to be involved in its evolution and propagation. In this study, we examined whether the nucleotide sequences of the 3' untranslated regions (UTRs) of the DNAs encoding the MBP are characteristic of MS. These genetic regions are presumed to be responsible for the transport and localization of the mRNAs encoding the MBP in the glia cells, thereby influencing the building up of the myelin sheaths of the glia cells.

T-251A polymorphism of IL-8 relating to the development of histological gastritis and G-308A polymorphism of TNF-alpha relating to the development of macroscopic erosion.

Objectives: Genetic variations of the inflammatory IL-8 and TNF-alpha genes can influence the outcome of gastric alterations. Our aims were to determine the prevalence and effect of the T-251A functional polymorphism of IL-8 and the G-308A polymorphism of TNF-alpha in histological and macroscopic gastric diseases related to Helicobacter pylori infection.

Methods: Genomic DNA was extracted from biopsy samples from patients with gastritis (n=86, H.