Different Kynurenine Pathway Dysregulation in Systemic Sclerosis in Men and Women.

Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc's inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences in KP activation among SSc patients and assess the impact of angiotensin-converting enzyme (ACE) inhibitors and estimated glomerular filtration rate (eGFR) on KP metabolite concentrations. We enrolled 48 SSc patients and 53 healthy controls, quantifying KP metabolites (tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA)) in serum via high-performance liquid chromatography. Separate multivariate analyses of covariance (MANCOVAs) for women and men were performed to ascertain mean differences between patients and healthy controls while correcting for age. For our secondary objective, we conducted a MANCOVA to explore disparities in ACE inhibitor users and non-users among patients, with BMI correction. Our findings revealed decreased TRP concentrations but increased KYNA/TRP ratio and KYN/TRP ratio in both male and female SSc patients compared to their respective controls. Unlike women, SSc males exhibited higher KYN concentrations and decreased KYNA/KYN ratio relative to their controls. Additionally, SSc patients using ACE inhibitors had higher serum KYNA levels than non-users. Notably, we established a significant correlation between eGFR and KYNA in SSc patients. These results indicate differential KP activation in male and female SSc patients, with males demonstrating heightened KP activation. While ACE inhibitors may influence the KP in SSc patients, further research is necessary to comprehensively understand their impact on symptoms and prognosis in the context of these KP alterations.

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets.

A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn's disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

6-Gingerol, a Major Constituent of Zingiber officinale Rhizoma, Exerts Anticonvulsant Activity in the Pentylenetetrazole-Induced Seizure Model in Larval Zebrafish.

Zingiber officinale is one of the most frequently used medicinal herbs in Asia. Using rodent seizure models, it was previously shown that Zingiber officinale hydroethanolic extract exerts antiseizure activity, but the active constituents responsible for this effect have not been determined. In this paper, we demonstrated that Zingiber officinale methanolic extract exerts anticonvulsant activity in the pentylenetetrazole (PTZ)-induced hyperlocomotion assay in larval zebrafish. Next, we isolated 6-gingerol (6-GIN)-a major constituent of Zingiber officinale rhizoma. We observed that 6-GIN exerted potent dose-dependent anticonvulsant activity in the PTZ-induced hyperlocomotion seizure assay in zebrafish, which was confirmed electroencephalographically. To obtain further insight into the molecular mechanisms of 6-GIN antiseizure activity, we assessed the concentration of two neurotransmitters in zebrafish, i.e., inhibitory γ-aminobutyric acid (GABA) and excitatory glutamic acid (GLU), and their ratio after exposure to acute PTZ dose. Here, 6-GIN decreased GLU level and reduced the GLU/GABA ratio in PTZ-treated fish compared with only PTZ-bathed fish. This activity was associated with the decrease in grin2b, but not gabra1a, grin1a, gria1a, gria2a, and gria3b expression in PTZ-treated fish. Molecular docking to the human NR2B-containing N-methyl-D-aspartate (NMDA) receptor suggests that 6-GIN might act as an inhibitor and interact with the amino terminal domain, the glutamate-binding site, as well as within the ion channel of the NR2B-containing NMDA receptor. In summary, our study reveals, for the first time, the anticonvulsant activity of 6-GIN. We suggest that this effect might at least be partially mediated by restoring the balance between GABA and GLU in the epileptic brain; however, more studies are needed to prove our hypothesis.

[Paraneoplastic rheumatologic syndromes in the elderly].

Risk of development of malignant tumors increases in elderly people. There are numerous clinical symptoms mimicking primary rheumatic diseases in the course of cancers, referred to as paraneoplastic rheumatologic syndromes. They are not caused directly by the tumor or its metastases, but result from the action of biologically active substances released by cancer cells and abnormal immunological reactions. Paraneoplastic rheumatologic syndromes may precede the diagnosis of cancer, occur simultaneously or occur after the diagnosis of malignancy. In clinical practice, it is very difficult to distinguish paraneoplastic syndromes from idiopathic rheumatic diseases. However, some clinical features may suggest the paraneoplastic nature of rheumatic diseases, including the onset of symptoms in old age, atypical and rapidly progressive course or poor response to conventional treatment. Early and well-targeted diagnostics allow the diagnosis of often latent neoplasm, and its effective treatment may lead to resolution of paraneoplastic rheumatic symptoms. This paper discusses selected paraneoplastic rheumatologic syndromes that often occur in older people, including carcinomatous polyarthritis, remitting seronegative symmetrical synovitis with pitting edema (RS3PE), palmar fasciitis-polyarthritis syndrome, hypertrophic osteoarthropathy, tumor-induced osteomalacia, cancerassociated myositis, paraneoplastic scleroderma like syndrome, paraneoplastic vasculitis and paraneoplastic Raynaud's syndrome.

[The changing face of medium-sized vasculitis].

Polyarteritis nodosa is a systemic necrotizing vasculitis which predominantly affects medium-sized arteries. It is a rare disease nowadays. Both the nomenclature and the classification of polyarteritis nodosa was amended several times in the past. Currently, there is a distinction between the primary form described as classical polyarteritis nodosa and other forms that are associated with their probable cause e.g. with viral hepatitis B, C or HIV infection. Moreover, polyarteritis-like necrotizing vasculitis can appear in the course of genetic diseases caused by mutations in single genes. The pathogenesis of idiopathic polyarteritis nodosa is still unclear, but a dominant role of the adaptive immune system disorders is suggested. Interestingly, in the hepatitis B virus-related vasculitis development, immune complexes are believed to play a crucial role. The spectrum of clinical manifestations of polyarteritis nodosa is wide, from involving a single organ to the polyvisceral failure. In the course of polyarteritis nodosa nearly each organ can be involved, however the disease never affects the lungs. Special forms of polyarteritis nodosa include a single-organ disease and a cutaneous form. The diagnosis of polyarteritis nodosa requires integration of clinical, angiographic and biopsy findings. Recognizing the form of polyarteritis nodosa, determining affected organs and the progression of the disease is very important since those are deciding factors when choosing treatment strategies.

[Cutaneous polyarteritis nodosa].

Cutaneous polyarteritis nodosa is a rare disease that affects vessels of the deep skin and the subcutaneous tissue. Its etiopathology remains unknown. It predominantly affects skin, and the main cutaneous symptoms are subcutaneous nodules, livedo reticularis, and ulcerations that are mainly located on legs. Cutaneous polyarteritis nodosa can also cause extracutaneous symptoms (fever, malaise, myalgias, arthralgias, neuropathy). It is a chronic benign disease with a relapsing course. Diagnostic criteria for this disease were recently proposed and both clinical and typical histological features must be present to confirm the diagnosis. Treatment of cutaneous polyarteritis nodosa depends on the severity of the disease and the frequency of relapses. Mild forms limited to skin lesions should be treated with nonsteroidal anti-inflammatory drugs, colchicine and locally applied glucocorticosteroids. Cases that are refractory to the treatment, that recur with extracutaneous symptoms may require applying more aggressive approach (glucocorticosteroids orally, hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil or intravenous immunoglobulins). The prognosis in cutaneous polyarteritis nodosa is favorable and the disease rarely turns into a systemic form.

[Contemporary diagnostics of the primary Sjögren's syndrome].

Primary Sjögren's syndrome is one of the most common systemic autoimmune disorders, whose diagnosis is very often delayed. In most cases it is a mild disease with symptoms such as dryness and musculoskeletal pain and fatigue but 20-40% of patients suffer from severe systemic manifestations. Extraglandular manifestations can be the first sign of the disease, therefore it is very important to diagnose them as early as possible. Classification criteria established by the American-European Consensus Group (AECG) have been applied in primary Sjögren's syndrome diagnosis since 2002. They took both subjective - dryness of eyes and mouth - and objective tests - imaging and functional tests of salivary glands, ocular tests, histopathologic test of minor salivary glands and presence of typical autoantibodies - into account. New classification criteria proposed in 2012 by the American College of Rheumatology (ACR) include objective tests only. Most recent research data suggest that noninvasive ultrasound examination of salivary gland should be included in the diagnostics process of Sjögren's syndrome due to its high specificity values which are comparable to those obtained from minor salivary glands biopsy. Also, it is important to evaluate disease activity in patients with primary Sjögren's syndrome using a score index - ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index).

Carotid surgery affects plasma kynurenic acid concentration: a pilot study.

BACKGROUND: An increase in plasma kynurenic acid (KYNA) concentration has been observed following surgery, inflammation, and cerebral pathologies. The aim of the present study was to analyze the changes in plasma KYNA concentration in patients undergoing carotid surgery (CS). MATERIAL AND METHODS: Adult patients undergoing elective carotid endarterectomy (CEA) or carotid angioplasty with stent placement (CAS) were studied. Plasma KYNA concentrations were analyzed before surgery and at 4 time points after CS. The amount of inflammation was measured as neutrophil-lymphocyte ratio (NLR). RESULTS: Forty patients (10 female and 30 male) aged 55-86 years of age were evaluated in this study. In patients with unstable carotid plaque, the plasma KYNA concentration was higher than in patients with stable carotid plaque. Moreover, the NLR was significantly higher in patients with unstable carotid plaque undergoing CEA than in patients undergoing CAS. Plasma KYNA concentration increased after surgery in patients undergoing CEA and CAS. There was a strong correlation between plasma KYNA concentration and NLR in patients with postoperative neurological disorders. CONCLUSIONS: CS increases plasma KYNA concentration, and changes in plasma KYNA concentration can indicate neurologic outcomes in patients undergoing CS.

[Kynurenic acid--a new tool in the treatment of hiperhomocysteinemia and its consequences?]. / Kwas kynureninowy--nowy orez w walce z hiperhomocysteinemia i jej nastepstwami?

Atherosclerosis together with its cardiovascular consequences is the most common and significant cause of death, particularly in highly developed countries. The process of atherogenesis begins as soon as in childhood and depends on classical risk factors. Atherosclerosis also results from a chronic inflammatory-immune process which takes place in the vascular walls. Furthermore, it has been known for a number of years that the development of atherosclerotic lesions is closely connected with the concentration of homocysteine in serum. Homocysteine is a sulfur amino acid originating from methionine. An increased concentration of homocysteine in blood harmfully influences blood vessels, leading to a higher risk of ischemic heart disease and stroke. Since tackling classical atherosclerosis risk factors is not efficient enough when it comes to protecting the cardiovascular system from diseases, new substances possessing anti-atherogenic properties, especially endogenous ones, are sought. Recently, researchers have paid attention to a connection between homocysteine and an endogenous tryptophan derivative, kynurenic acid. Recently, it was revealed that kynurenic acid counteracts the harmful effects of homocysteine on endothelium cells in vitro. The hypothesis assuming homocysteine-kynurenate interplay suggests the existence of a new mechanism of atherogenesis and gives us an opportunity to use this knowledge in both prevention and treatment of cardiovascular diseases.

A Review of the Health Benefits of Food Enriched with Kynurenic Acid.

Kynurenic acid (KYNA), a metabolite of tryptophan, is an endogenous substance produced intracellularly by various human cells. In addition, KYNA can be synthesized by the gut microbiome and delivered in food. However, its content in food is very low and the total alimentary supply with food accounts for only 1-3% of daily KYNA excretion. The only known exception is chestnut honey, which has a higher KYNA content than other foods by at least two orders of magnitude. KYNA is readily absorbed from the gastrointestinal tract; it is not metabolized and is excreted mainly in urine. It possesses well-defined molecular targets, which allows the study and elucidation of KYNA's role in various pathological conditions. Following a period of fascination with KYNA's importance for the central nervous system, research into its role in the peripheral system has been expanding rapidly in recent years, bringing some exciting discoveries. KYNA does not penetrate from the peripheral circulation into the brain; hence, the following review summarizes knowledge on the peripheral consequences of KYNA administration, presents data on KYNA content in food products, in the context of its daily supply in diets, and systematizes the available pharmacokinetic data. Finally, it provides an analysis of the rationale behind enriching foods with KYNA for health-promoting effects.

Paraoxonase 1 Phenotype and Protein N-Homocysteinylation in Patients with Rheumatoid Arthritis: Implications for Cardiovascular Disease.

Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the development of atherosclerosis by metabolizing lipid peroxidation products as well as hydrolyzing proatherogenic metabolite of homocysteine (Hcy), Hcy thiolactone, which otherwise reacts with lysine groups of proteins, thus forming N-Hcy-protein in a process referred to as protein N-homocysteinylation. Rheumatoid arthritis (RA) is the chronic inflammatory autoimmune disease associated with increased risk of cardiovascular complications, but the underlying mechanisms are incompletely understood. We examined PON1 status and N-homocysteinylation of serum proteins in patients with RA. Blood was collected from 74 RA patients and 70 control subjects. PON1 activity was measured toward synthetic (paraoxon, phenyl acetate) and natural (Hcy thiolactone) substrates. PON1 protein concentration was measured by ELISA. Total Hcy as well as N-Hcy-protein were measured in serum as well. PON1 activity toward Hcy thiolactone was lower in RA patients than in control subjects which was accompanied by increased concentration of N-Hcy-protein despite normal total Hcy concentration. PON1 protein concentration was unchanged in the RA group, but the specific enzyme activity was reduced. When RA patients were categorized according to the DAS28-ESR score, PON1 concentration and enzymatic activity were lower whereas N-Hcy-protein was higher in those with high disease activity. PON1 activity and Hcy thiolactone were correlated with DAS28-ESR score and myeloperoxidase concentration. In conclusion, RA is associated with deficiency of PON1 activity and increased protein N-homocyseinylation which may contribute to accelerated development of cardiovascular diseases.

Chronic dietary supplementation with kynurenic acid, a neuroactive metabolite of tryptophan, decreased body weight without negative influence on densitometry and mandibular bone biomechanical endurance in young rats.

Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan. KYNA naturally occurs in breast milk and its content increases with lactation, indicating the role of neonatal nutrition in general growth with long-term health effects. KYNA is also an antagonist of ionotropic glutamate receptors expressed in bone cells. The aim of this study was to establish the effects of chronic KYNA supplementation on bone homeostasis in young rats, using mandible as a model bone. Female and male newborn Wistar rats were divided into control and KYNA-administered groups until 60 days of age (25x101 mg/L or 25x102 mg/L in drinking water). Hemimandibles were subjected to densitometry, computed tomography analysis and mechanical testing. Rats supplemented with KYNA at both doses showed a decrease in body weight. There were no effects of KYNA administration and mandible histomorphometry. In males, a significant quadratic effect (P < 0.001) was observed in the densitometry of the hemimandible, where BMD increased in the group supplemented with 2.5x101 mg/L of KYNA. Analysis of mechanical tests data showed that when fracture forces were corrected for bone geometry and rats body weight the improvement of bone material properties was observed in male and female rats supplemented with lower dose of KYNA. This study showed that chronic supplementation with KYNA may limit weight gain in the young, without adversely affecting the development of the skeleton.

Parthenolide inhibits proliferation of fibroblast-like synoviocytes in vitro.

Parthenolide is a bioactive constituent of an aromatic herb Feverfew (Tanacetum parthenium). It has been found that both parthenolide and extract of feverfew have anti-inflammatory and antinociceptive properties. Moreover, they demonstrate antiproliferative activities on different human tumour cells. The massive hyperplasia of synovial fibroblasts is the one of the most striking features of rheumatoid arthritis. It is not known whether this is due to the proliferation of synovial fibroblasts or to defective apoptosis. We investigated the effect of parthenolide on the proliferation of rabbit synoviocytes cell line HIG-82, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and human skin fibroblasts (HSF) in vitro. Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 5'-bromo-2'-deoxy-uridine methods. Parthenolide inhibited proliferation of HIG-82 and human RA-FLS. The proliferation of HSF was inhibited less effectively. The antiproliferative potential of parthenolide was demonstrated.

Quinaldic acid in synovial fluid of patients with rheumatoid arthritis and osteoarthritis and its effect on synoviocytes in vitro.

BACKGROUND: Previously, we have demonstrated that kynurenic acid (KYNA), an endogenous metabolite of tryptophan formed along kynurenine pathway, is present in synovial fluid of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. In this study, the goal was to investigate the presence of quinaldic acid (QUDA), a putative metabolite of KYNA, in synovial fluid of RA and OA patients. METHODS: The effect of QUDA on proliferation and motility of synovial fibroblasts and its interaction with KYNA were determined in vitro. The study was conducted on synovial fluid obtained from 38 patients with RA and 15 patients with OA. QUDA was identified and quantified using the gas chromatography-mass spectrometry (GC-MS) method. In vitro experiments were conducted on rabbit synoviocyte cell line HIG-82. RESULTS: Presence of QUDA was detected in all 53 samples of synovial fluid. The concentration of QUDA in synovial fluid obtained from patients with RA was 28.6 ±â€¯14.9 pmol/ml, which was lower in comparison with OA 42.3 ±â€¯10.0 pmol/ml. QUDA content positively correlated with the number of tender joints and negatively with the total cell counts determined in synovial fluid of RA patients. It did not correlate with KYNA content. QUDA reduced both proliferation and motility of synoviocytes in a dose-dependent manner. The enhancement of antiproliferative action of QUDA by KYNA was evidenced. CONCLUSIONS: Data show a local deficit of QUDA in RA patients and suggest its potential role as an endogenous substance controlling synoviocyte viability.

Kynurenic Acid Protects against Thioacetamide-Induced Liver Injury in Rats.

Acute liver failure (ALF) is a life-threatening disorder of liver function. Kynurenic acid (KYNA), a tryptophan metabolite formed along the kynurenine metabolic pathway, possesses anti-inflammatory and antioxidant properties. Its presence in food and its potential role in the digestive system was recently reported. The aim of this study was to define the effect of KYNA on liver failure. The Wistar rat model of thioacetamide-induced liver injury was used. Morphological and biochemical analyses as well as the measurement of KYNA content in liver and hepatoprotective herbal remedies were conducted. The significant attenuation of morphological disturbances and aspartate and alanine transaminase activities, decrease of myeloperoxidase and tumor necrosis factor-α, and elevation of interleukin-10 levels indicating the protective effect of KYNA in thioacetamide (TAA) - induced liver injury were discovered. In conclusion, the hepatoprotective role of KYNA in an animal model of liver failure was documented and the use of KYNA in the treatment of ALF was suggested.

Antiproliferative activity of parthenolide against three human cancer cell lines and human umbilical vein endothelial cells.

Parthenolide is a major sesquiterpene lactone derived from feverfew (Tanacetum parthenium) with known anti-inflammatory activity. Moreover, the anticancer potential of this compound was suggested. In this study, we determined the effect of parthenolide on proliferation of three human cancer cell lines: human lung carcinoma (A549), human medulloblastoma (TE671), human colon adenocarcinoma (HT-29) and human umbilical vein endothelial cells (HUVEC) in vitro. Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC(50) value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. Parthenolide inhibited proliferation of all three types of cancer cells (A549, TE671, HT-29) and HUVEC with the following IC(50) values (in muM): 4.3, 6.5, 7.0 and 2.8, respectively. Thus, the antiproliferative potential of parthenolide was confirmed.

Influence of picolinic acid on seizure susceptibility in mice.

BACKGROUND: The mechanism of drug resistance in epilepsy remains unknown. Picolinic acid (PIC) is an endogenous metabolite of the kynurenine pathway and a chelating agent added to dietary supplements. Both inhibitory and excitatory properties of PIC were reported. The aim of this study was to determine the influence of exogenously applied PIC upon the electroconvulsive threshold and the activity of chemical convulsants in eight models of epilepsy in mice. METHODS: All experiments were performed on adult male Swiss albino mice. Electroconvulsions were induced through ear clip electrodes. The electroconvulsive threshold (current strength necessary to induce tonic seizures in 50% of the tested group - CS50) was estimated for control animals and animals pretreated with PIC. To determine the possible convulsant activity of PIC, it was administered subcutaneously or intracerebroventricularly in increasing doses to calculate the CD50 values (doses of convulsants necessary to produce seizures in 50% of the animals). Chemical convulsions were induced by challenging the animals with increasing doses of convulsant to calculate the CD50 values. The following convulsants were used: 4-aminopyridine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, bicuculline, N-methyl-d-aspartate, nicotine, pentylenetrazole, pilocarpine hydrochloride and strychnine nitrate. RESULTS: PIC significantly decreased the electroconvulsive threshold and, after intracerebroventricular injection, but not subcutaneous, produced convulsions. Of the studied convulsants, only the activity of pilocarpine hydrochloride was significantly enhanced by PIC. CONCLUSIONS: PIC enhances seizure activity and potentially may play a role in the pathogenesis of drug resistant epilepsy. Future studies should focus on the interactions between PIC and antiepileptic drugs.

Effect of glutamate receptor antagonists and antirheumatic drugs on proliferation of synoviocytes in vitro.

One of the most striking features of inflammatory arthritis is the hyperplasia of synovial fibroblasts. It is not known whether the massive synovial hyperplasia characteristic of rheumatoid arthritis is due to the proliferation of synovial fibroblasts or to defective apoptosis. It has been found that glutamate receptor antagonists inhibit proliferation of different human tumour cells and the anticancer potential of glutamate receptor antagonists was suggested. Here, we investigated the effect of glutamate receptor antagonists and selected antirheumatic drugs on proliferation of synoviocytes in vitro. Experiments were conducted on rabbit synoviocytes cell line HIG-82 obtained from American Type Culture Collection (Menassas, VA, USA). Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. Glutamate receptor antagonists, 1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (CFM-2), riluzole, memantine, 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), dizocilpine, ketamine and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.014, 0.017, 0.065, 0.102, 0.15, 0.435 and 1.16, respectively. Antirheumatic drugs, celecoxib, diclofenac, nimesulide, sulfasalazine, naproxen and methotrexate, inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.0043, 0.034, 0.044, 0.096, 0.385 and 1.123, respectively. Thus, the antiproliferative potential of glutamate receptor antagonists is comparable to that of antirheumatic drugs.

Kynurenic acid in human saliva--does it influence oral microflora?

Kynurenic acid (KYNA) is an endogenous antagonist of alpha7 nicotinic receptors and all ionotropic glutamate receptors. Its neuroprotective activity has been suggested. In this study, the presence of KYNAin human saliva and its potential bactericidal role was investigated. KYNAwas found in all samples of human saliva with mean concentration of 3.4 nM. The concentration of KYNA in saliva obtained from patients with odontogenic abscesses was 3.5 times higher than in healthy subjects. We have shown that the human gingival fibroblasts produce KYNAand an inflammatory stimulant, lipopolysaccharide, enhanced its synthesis in vitro. The bactericidal effect of KYNA was also presented. We hypothesize that KYNA may contribute to the control of oral microflora.

[Prolactin in connective tissue diseases]. / Prolaktyna w ukladowych chorobach tkanki lacznej.

This paper presents interactions between prolactin (PRL) and the immune system. We describe the role of PRL in the pathogenesis of rheumatic diseases, particularly connective tissue diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome, systemic sclerosis, polymyalgia rheumatica, and seronegative arthritis. We present current opinion on the mechanisms responsible for hyperprolactinemia in SLE patients and the association between hyperprolactinemia and SLE activity and organ involvement. The role of dopamine receptor agonists in the treatment of connective tissue diseases is discussed.