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Introduction The primary objective of our study was to explore the changes of antioxidant, inflammatory, and metabolic parameters in obese and hypertension people patients during balneotherapy and to evaluate the safety of balneotherapy in these participants. Methods Following randomisation, 22 obese and 20 hypertensive patients underwent balneotherapy with thermal water of 38 °C temperature, in 15 sessions of 30 minutes. An additional 22 obese and 20 hypertensive patients served as controls. Antioxidant, inflammatory, and metabolic parameters were determined at baseline, as well as post-treatment and at the end of follow-up (at 15 weeks). Results As regards changes observed in hypertensive patients subjected to balneotherapy, differences could be detected between baseline and post-treatment albumin and haemoglobin A 1c levels only; however, these were no longer significant after 3 months. Although the difference between transferrin levels determined at the end of balneotherapy and 3 months later was significant, it remained within the physiological range, as well as it was accompanied by normal serum iron level and therefore, it was considered irrelevant. C-reactive protein levels of balneotherapy patients decreased significantly after treatment. In obese patients, haemoglobin A 1c level decreased after balneotherapy, but this difference was not observed either after 3 months. Similarly, both transferrin and C-reactive protein levels changed from baseline, but not between groups. Conclusions This study contributes important information regarding the safety of balneotherapy in hypertensive and obese diabetics by showing no alterations of antioxidant, inflammatory, or metabolic indices. The findings of this study confirm that balneotherapy is not contraindicated for hypertensive or obese patients.

Experimental and clinical evidence for T cell involvement in the pathology of rheumatoid arthritis (RA) is compelling, and points to a local dysregulation of T cell function in the inflamed joint. Nitric oxide (NO) has been shown to regulate T cell function under physiological conditions, but overproduction of NO may contribute to lymphocyte dysfunction characteristic of RA. Several investigations in patients with RA have documented evidence of increased NO synthesis, but these studies have focused largely on macrophage-derived NO and its impact on innate immune and inflammatory responses. In this study, we set out to explore the contribution that T cells make to NO production. We find that T cells from RA patients produce2.5 times more NO than healthy donor T cells (p0.001). Although NO is an important physiological mediator of mitochondrial biogenesis, mitochondrial mass is similar in RA and control T cells. In contrast, increased NO production is associated with increased cytoplasmic Ca(2+) concentrations in RA T cells (p0.001). In vitro treatment of human peripheral blood lymphocytes, or Jurkat cells with TNF increases NO production (p=0.006 and p=0.001, respectively), whilst infliximab treatment in RA patients decreases T cell derived NO production within 6 weeks of the first infusion (p=0.005). Together, these data indicate that TNF induced NO production in T lymphocytes may contribute to perturbations of immune homeostasis in RA.

T lymphocyte activation is associated with nitric oxide (NO) production, which plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both activation and apoptosis of Tlymphocytes, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus induces mitochondrial biogenesis and alters Ca(2+) signaling. Thus, whereas NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity.

Activation, proliferation, or programmed cell death of T lymphocytes is regulated by the mitochondrial transmembrane potential (Δψm) through controlling ATP synthesis, production of reactive oxygen intermediates (ROI), and release of cell death-inducing factors. Elevation of Δψm or mitochondrial hyperpolarization is an early and reversible event associated with both T cell activation and apoptosis. In the present study, T cell activation signals leading to mitochondrial hyperpolarization were investigated. CD3/CD28 costimulation of human PBL elevated cytoplasmic and mitochondrial Ca2+ levels, ROI production, and NO production, and elicited mitochondrial hyperpolarization. Although T cell activation-induced Ca2+ release, ROI levels, and NO production were diminished by inositol 1,4,5-triphosphate receptor antagonist 2-aminoethoxydiphenyl borane, superoxide dismutase mimic manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, spin trap 5-diisopropoxyphosphoryl-5-methyl-1-pyrroline-N-oxide, and NO chelator carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, mitochondrial hyperpolarization was selectively inhibited by carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (−85.0 ± 10.0%; p = 0.008) and, to a lesser extent, by 2-aminoethoxydiphenyl borane. Moreover, NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate diethylenetriamine elicited NO and ROI production, Ca2+ release, transient ATP depletion, and robust mitochondrial hyperpolarization (3.5 ± 0.8-fold; p = 0.002). Western blot analysis revealed expression of Ca-dependent endothelial NO synthase and neuronal NO synthase isoforms and absence of Ca-independent inducible NO synthase in PBL. CD3/CD28 costimulation or H2O2 elicited severalfold elevations of endothelial NO synthase and neuronal NO synthase expression, as compared with β-actin. H2O2 also led to moderate mitochondrial hyperpolarization; however, Ca2+ influx by ionomycin or Ca2+ release from intracellular stores by thapsigargin alone failed to induce NO synthase expression, NO production, or Δψm elevation. The results suggest that T cell activation-induced mitochondrial hyperpolarization is mediated by ROI- and Ca2+-dependent NO production.

An increasing body of evidence substantiating the effectiveness of balneotherapy has accumulated during recent decades. In the present study, 42 ambulatory patients (23 males and 19 females, mean age 59.5 years) with degenerative musculoskeletal disease were randomised into one of two groups—bathing in tap water or in mineral water at the same temperature—and subjected to 30-min balneotherapy sessions on 15 occasions. Study parameters comprised serum levels of sensitised C-reactive protein (CRP), plasma lipids, heat shock protein (HSP-60) and total antioxidant status (TAS). In both groups, CRP levels followed a decreasing tendency, which still persisted 3 months later. At 3 months after balneotherapy, serum cholesterol levels were still decreasing in patients who had used medicinal water, but exhibited a trend towards an increase in the control group. Triglyceride levels followed a decreasing trend in both patient groups. TAS showed a declining tendency in both groups. No changes of HSP-60 levels were observed in either group. Balneotherapy with the thermal water from Hajduszoboszlo spa had a more pronounced physiological effect compared to that seen in the control group treated with tap water in a 3 month period.

Histamine is a key regulator of the immune system. Several lines of evidence suggest the role of histamine in T cell activation and accelerated Th1 immune response is a hallmark of histidine decarboxylase knockout (HDC-KO) mice, with a complete lack of endogenously produced histamine. According to our previous work, T lymphocytes produce NO upon activation, and NO is necessary for effective T cell activation. To study the role of histamine in T cell activation, we investigated cytokine production and T cell signal transduction in HDC-KO and wild-type (WT) mice. In the absence of histamine, an elevated IFN-γ mRNA and protein levels of splenocytes (p < 0.001; p = 0.001, respectively) were associated with a markedly increased (2.5-fold, p = 0.0009) NO production, compared with WT animals. Furthermore, histamine treatment decreased the NO production of splenocytes from both WT and HDC-KO mice (p = 0.001; p = 0.0004, respectively). NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2-diolate-diethylenetriamine elicited IFN-γ production (p = 0.0002), whereas NO synthase inhibitors NG-monomethyl-l-arginine and nitronidazole both inhibited IFN-γ production (p = 0.002 and p = 0.01, respectively), suggesting the role of NO in regulating IFN-γ synthesis. Cytoplasmic Ca2+ concentration of unstimulated T cells was increased in the HDC-KO mice (p = 0.02), whereas T cell activation-induced δ Ca2+-signal was similar in both HDC-KO and WT animals. Our present data indicate that, in addition to its direct effects on T lymphocyte function, histamine regulates cytokine production and T cell signal transduction through regulating NO production.

Increased numbers of mast cells are found in the synovial tissues and fluids of patients with rheumatoid arthritis, and at sites of cartilage erosion. Mast cell activation has been reported for a significant proportion of rheumatoid specimens. Because the mast cell contains potent mediators, including histamine, its potential contributions to the processes of inflammation and matrix degradation have recently become evident; thereafter, we investigated the potential protective effect of histamine deficiency against aggrecan-induced arthritis. To study the role of histamine in rheumatoid arthritis we investigated cartilage proteoglycan (aggrecan)-induced arthritis in histidine decarboxylase knockout (HDC-KO) mice, with complete lack of endogenously produced histamine. Aggrecan-induced arthritis was similar in HDC-KO and wild-type (WT) mice. Arthritis was even more severe in HDC-KO mice than in the WT animals 10 weeks following the immunization with aggrecan (arthritis score 1.2 ± 1.5 and 0 ± 0, respectively; P = 0.01). At later time points, arthritis scores were similar in both HDC-KO and WT mice. Since T-lymphocyte dysfunction has an important role in the pathogenesis of rheumatoid arthritis, next we investigated T-cell signal transduction and cytokine production in HDC-KO and WT mice. In the absence of histamine, elevated INFγ mRNA and protein levels of splenocytes (P < 0.001 and P = 0.001, respectively) were associated with a markedly increased (2.5-fold, P = 0.0009) nitric oxide (NO) production, compared with WT animals. Furthermore, histamine treatment decreased the NO production of splenocytes from both WT and HDC-KO mice (P = 0.001 and P = 0.0004, respectively). NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate-diethylenetriamine (NOC-18) elicited IFNγ production (P = 0.0002), suggesting the role of NO in regulating IFNγ synthesis. The cytoplasmic Ca2+ concentration of unstimulated T cells and the T-cell activation-induced Ca2+ signal were increased in T cells from the HDC-KO mice (P = 0.02 and P = 0.04, respectively), while the T-cell activation-induced CD3 internalization was similar in both HDC-KO and WT animals. Our present data indicate that histamine deficiency does not protect against aggrecan-induced arthritis. The Th1 cytokine pattern and increased NO production may both contribute to the sensitivity of HDC-KO mice to aggrecan-induced arthritis. Furthermore, our data indicate that histamine, in addition to its direct effects on T-lymphocyte function, regulates cytokine production and T-cell signal transduction through regulating NO production.