Introduction
Materials and methods
Results
In vitro studies on human samples evaluating the beneficial effects of BT on immune response in skin diseases
Authors | Journal | Pathology | Experimental model | Treatment | Mineral water or inorganic or organic components | Biochemicalparameters | Results |
---|---|---|---|---|---|---|---|
Gobbi et al. 2009 [6] | Lab Investig | Psoriasis | Normal skin-derived immortalized human keratinocytes | 30-min preincubation with MAPK/ERK inhibitors (10–30 μM) + NaHS (400 mM) dissolved in the culture medium, for 6, 12, 18, 24 h | NaHS | Cell proliferation and adhesion; MAPK/ERK signaling Phosphorylation | ↓keratinocyte cell growth and adhesion ↓MAPK/ERK phosphorylation ↓inflammation |
Mirandola et al. 2011 [7] | Lab Investig | Psoriasis | Normal skin-derived immortalized human keratinocytes | 30-min preincubation with MAPK/ERK inhibitors (10–30 μM) + NaHS (400 mM) dissolved in the culture medium, for 6, 12, 18, 24 h | NaHS | IL-8; MAPK/ERK signaling phosphorylation | ↓ basal and IL-17/IL-22-induced IL-8 expression and secretion ↓ MAPK/ERK phosphorylation ↓ inflammation |
Chiarini et al. 2006 [8] | Int J Mol Med | Psoriasis | Human primary epidermal keratinocytes | 25%, 50%, or 100% of Comano water dissolved in the culture medium, for 11 days | Comano spa’s water (Trentino, Italy), rich in sodium, calcium and bicarbonate | VEGF-A | ↓ VEGF-A ↓ VEGF-A-mediated effects |
Chiarini et al. 2006 [9] | Int J Mol Med | Psoriasis | Human primary epidermal keratinocytes | 25%, 50%, or 100% of Comano water dissolved in the culture medium, from 3 to 15 days | Comano spa’s water (Trentino, Italy), rich in sodium, calcium and bicarbonate | IL-6, CK-16, VEGF-A | ↓ IL-6, VEGF, and CK-16 release and expression ↓ inflammation, and neo-angiogenic phenomena |
Dal Pra et al. 2007 [10] | Int J Mol Med | Psoriasis | Human primary epidermal keratinocytes | 25%, 50%, or 100% of Comano water dissolved in the culture medium, from 11 to 13 days | Comano spa’s water (Trentino, Italy), rich in sodium, calcium and bicarbonate | IL-8, TNF-α | ↓ IL-8 and TNF-α ↓ inflammation |
Karagülle et al. 2018 [11] | Int J Biometeorol | Psoriasis and rosacea | Human keratinocyte cell lines | 10% of Bursa and Bolu thermal mineral waters dissolved in the culture medium, for 3 days | IL-1α, TNF-α, and VEGF | ↓ IL-1α, TNF-α, and VEGF gene expression ↓ inflammation, and neo-angiogenic phenomena | |
Lee et al. 2012 [12] | Ann Dermatol | Skin disease | Human keratinocyte cell lines | 50% of Yong-gung oncheon thermal spring water dissolved in the culture medium, for 1, 4, 10, and 24 h + LPS (10 μL/mL) | HaCaT Thermal spring water (Yong-gung oncheon, Ganghwa-gun, Korea), rich in sulfur, magnesium, calcium and selenium | IL-6, IL-8; CD4 + T cell differentiation | ↓ IL-6 and IL-8 gene and protein expression ↓ differentiation of CD4 + T cells in Th1, Th2 and Th17 ↓ immune skin reactions |
In vitro studies on human samples evaluating the beneficial effects of BT on immune response in musculoskeletal diseases
Authors | Journal | Pathology | Experimental model | Treatment | Mineral water or inorganic or organic components | Biochemicalparameters | Results | ||||||||
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Fox et al. 2012 [13] | J Cell Mol Med | RA | Human primary articular chondrocytes | IL-1β, IL-6 and TNF-α (5 ng/mL) for 6, 12 and 18 h + GYY4137 (50–500 mol/L) dissolved in the culture medium, for 12 h | GYY4137 | Cell death; Mitochondrial membrane potential | ↓ cell death and oxidant-induced mitochondrial dysfunction ↓ inflammation | ||||||||
Li et al. 2013 [14] | J Cell Mol Med | RA | Human primary arthritis synoviocytes and chondrocytes | (0.1–0.5 mM) dissolved in the culture medium, for 18 h + LPS (10 μg/mL) | GYY4137 | ↓ IL-6, TNF-α, PGE2 and NO production ↓ COX-2 and iNOS catalytic activity ↓ NF-kB activation ↓ inflammatory processes | |||||||||
Burguera et al. 2014 [15] | Osteoarthr Cartil | OA | Human primary OA chondrocytes | NaHS and GYY4137 (0.05–1 mM) dissolved in the culture medium, for 24 or 48 h + IL-1β (5 ng/mL) | NaHS and GYY4137 | IL-6, PGE2, PTGES, COX-2; NO, NOS2; MMP-13; NF-kB signaling activation | ↓ IL-6, PGE2, and NO release and protein level ↓ IL-6, PTGES, COX-2, and NOS2 gene expression ↓ NF-κB nuclear translocation ↓ inflammatory and degrading processes | ||||||||
Ha et al. 2015 [16] | Int J MolMed | OA | Human primary OA chondrocytes | NaHS (0.06–1.5 mM) dissolved in the culture medium, for 24 h + IL-1β (10 ng/mL) | NaHS | COX-2, iNOS, MMP-13; ERK/IκBα/NF-κB signaling activation | ↓ COX-2, iNOS, MMP-13 release and gene expression ↓ERK/IκBα/NF-κB activation ↓ degrading processes | ||||||||
Sieghart et al. 2015 [18] | J Cell Mol Med | Human primary OA fibroblast-like synoviocytes | NaHS (0.06–1 mmol/L) dissolved in the culture medium, for 1 h + IL-1β (10 ng/mL) | NaHS | IL-6, IL-8; MMP-2, MMP-14; MAPK and Akt1/2/PI3K protein phosphorylation | ↓ IL-6 and IL-8 secretion, MMP-2 and MMP-14 gene expression ↓ MAPK phosphorylation ↑ Akt1/2 phosphorylation ↓ inflammatory and degrading processes | |||||||||
Vela-Anero et al. 2017 [19] | Nitric Oxide | OA | Human OA cartilage disks | NaHS or GYY4137 (200 or 1000 μM) dissolved in the culture medium, for 21 days + IL-1β (5 ng/mL) | NaHS and GYY4137 | MMP-3, MMP-13; COL2A1, glycosaminoglycans, aggrecans | ↓ MMP-3 and MMP-13 production ↑ COL2A1, glycosaminoglycans and aggrecans synthesis ↓ degrading processes | ||||||||
Fioravanti et al. 2013 [17] | J Biol Regul Homeost Agents | OA | Human primary OA chondrocytes | 25%, 50%, or 100% of Vetriolo thermal water dissolved in the culture medium, for 48 h + IL-1β (5 ng/mL) | Vetriolo thermal water (Trentino Alto Adige Italy), strongly acidic sulfate, rich in calcium, magnesium and iron | NO, iNOS; Cell viability and apoptosis; Morphological assessment | 25%, 50% of Vetriolo water ↑ survival recovery rate ↓ NO levels, iNOS expressions, and apoptosis ↑ morphological characteristics ↓ degrading processes | ||||||||
Kloesch et al. 2010 [20] | Cell Biol Int | RA | fibroblast-like synoviocytes | NaHS (200 mM) | NaHS | IL-6; activation/deactivation of MAPKs; p38 and p44/42 MAPK (ERK1/2) | ↓ IL-1β-induced expression of IL-6 with low concentrations of NaHS H2S deactivates p44/42 MAPK (ERK1/2) ↑ activation of p38 MAPK, ERK1/2 and IL-6 with long-term exposure to H2S | ||||||||
Kloesch et al. 2012 [21] | Immunol Lett | RA and OA | RA and OA human fibroblast- like synoviocytes | NaHS (1.0 mM) dissolved in the culture medium, for 1, 3, 6, 12 h | NaHS | IL-6, IL-8, COX-2; MMP-2, MMP-3, MMP-14; p38/MAPK/ERK protein expression | ↑ IL-6, IL-8, COX-2 and p38/MAPK/ERK expression | ||||||||
Kloesch et al. 2012 [22] | Rheumatol Int | RA | Human chondrocyte cell line | NaHS (0.125 and 1.0 mM) dissolved in the culture medium, for 15, 30, 45 and 60 min + MAPK inhibitors (1 and 5 μM) + IL-1β(5 ng/mL) for 1 h | NaHS | IL-6, IL-8; P38/MAPK/ERK and NF-kB signaling activation/- deactivation | ↓ IL-6 and IL-8 ↓ p38/MAPK/ERK ↓ NF-kB signalling ↓ inflammatory processes | ||||||||
Gambari et al. 2014 [23] | Pharmacol Res | Osteoporosis | Human differentiated osteoclasts | NaHS (50–300 μM) dissolved in the culture medium, for 72 h to 6 days | NaHS | Osteoclasts differentiation; ROS production, NRF2, KEAP1, NQO1, and PRDX1 | ↓ osteoclast differentiation ↓ intracellular ROS levels ↑ NRF2 protein expression and nuclear translocation ↑ antioxidant gene |
In vitro studies on animal samples evaluating the beneficial effects of BT on immune response in musculoskeletal diseases
Authors | Journal | Pathology | Experimental model | Treatment | Mineral water or inorganic or organic components | Biochemicalparameters | Results |
---|---|---|---|---|---|---|---|
Xu et al. 2011 [24] | Free Radic Biol Med | Osteoporosis | Murine osteoblast-like cell line (MC3T3-E1) | NaHS (100 μM) dissolved in the culture medium, for 4 h + (H2O2) (400 μM) | NaHS | Viability, proliferation and apoptosis; NO, ALP, SOD, NADPH oxidase p38/ERK1/2/MAPKs activation | ↑ viability ↑ cell proliferation ↑ ALP and SOD activities ↓ apoptosis ↓ NO release ↓ NADPH oxidase activity ↓ p38/ ERK1/2/ MAPKs activation Proliferative and antioxidant effects against osteoporosis damage |
Lv et al. 2017 [25] | Am J Transl Res | Osteoporosis | Murine osteoblast-like cell line (MC3T3-E1) | GYY4137 (100 μM) dissolved in the culture medium, for 4 h + (H2O2) (400 μM) | GYY4137 | Viability, proliferation, Runx2, and apoptosis; NO, ALP, and SOD, ERK1/2 activation | ↑ viability ↑ cell proliferation ↑ ALP and SOD activities ↑ Runx2 gene expression ↓ apoptosis ↓ NO release ↓ ERK1/2 activation Proliferative and antioxidant effects |
Liu et al. 2017 [26] | Biochimie | Osteoporosis | Rat primary osteoblasts | NaHS (400 μmol/L) dissolved in the culture medium, for 12 h | NaHS | Osteoblast proliferation and mineralization; Apoptosis; KATP protein expression | ↓ cell proliferation ↑ apoptotic cells ↑ osteoblast mineralization ↑ KATP protein expression ↓ osteoporosis damage |
In vitro studies on human samples evaluating the beneficial effects of BT on immune response in inflammatory diseases
Authors | Journal | Treatment | Experimental model | Mineral water or inorganic or organic components | Pathology | Biochemicalparameters | Results |
---|---|---|---|---|---|---|---|
Rinaldi et al. 2006 [27] | Lab Investig | NaHS (from 0.23 to 3.66 mM) dissolved in the culture medium, for 24 h + p38/MAPK inhibitors (30–60 μM) | Human purified neutrophils, eosinophils or lymphocytes | NaHS | Inflammatory processes of respiratory tract | Cell viability and apoptosis; p38/MAPK signaling activation/deactivation | ↑ Short-term survival of neutrophils ↓ caspase-3 cleavage and p38/MAPK phosphorylation in neutrophils Accelerate the resolution of inflammatory processes |
Mirandola et al. 2007 [28] | J Cell Physiol | NaHS (from 0.20 to 4.0 mM) dissolved in the culture medium, for 24 h + caspase inhibitors (30 μM) | Human purified peripheral blood lymphocytes | NaHS | Inflammatory processes | Cell viability and apoptosis; IL-2 | ↓ proliferation of lymphocyte subsets ↓ D8 + T and NK cells ↓ IL-2 production Accelerate the resolution of inflammatory processes |
Sulen et al. 2016 [29] | Pharmacol Res | NaHS (10, 100 or 1000 μM) dissolved in the culture medium, for 10 min | Human peripheral blood mononuclear cells (PBMCs) | NaHS | Inflammatory processes | p38/MAPK, NF-κB p65, Akt and CREB phosphorylation | ↑ p38/MAPK, Akt, and CREB phosphorylation ↓ inflammatory processes |
Han et al. 2013 [30] | Cell Physiol Biochem | NaHS (0.25, 0.5, 1, 2, 4 and 8 mM) and GYY4137 (200, 400, 800, 1600 μM) dissolved in the culture medium, for 0.5, 1, 2, 4, 6, 12, 24, 36, 48 h | Human purified peripheral blood lymphocytes | NaHS and GYY4137 | Inflammatory processes of systemic lupus erythematosus | Cell viability, cell cycle distribution; Akt (ser473), GSK3β (ser9), p27Kip1 and p21CIP1 | ↑ cell proliferation and S phase distribution of cell cycle ↓ Akt (ser473), GSK (ser9) ↑ p27Kip1 and p21CIP1 expression and phosphorylation ↓ inflammatory processes |
Braga et al. 2008 [31] | Respiration | Sulfurous thermal water (different concentrations) dissolved in the culture medium, for 15 min + N-formyl-methionyl-leucyl-phenylalanine/phorbol-12-myristate-13-acetate | Human purified neutrophils | Sulfurous thermal water (Acqui Terme, Piemonte, Italy), which contains different HS groups concentrations | Inflammatory processes | ROS and RNS | ↓ ROS and RNS release at 0.94 to 15.5 μg/mL of HS ↓ inflammatoryprocesses |
Braga et al. 2010 [32] | TherAdvRespirDis | Sulfurous water or NaHS (from 4.5 to 18 mg/mL) dissolved in the culture medium, for 15 min | Human purified neutrophils | Sulfurous thermal water (AcquiTerme, Piemonte, Italy) and NaHS | Inflammatory processes of upper and lower airway diseases | Elastase release; elastolyticactivity | Inhibited elastase release ↓ inflammatory processes |
Prandelli et al. 2013 [23] | Int J ImmunopatholPharmacol | Sirmione thermal water or NaHS (2.5 mM) dissolved in the culture medium, for 24 h + LPS (100 ng/mL) | Human primary monocytes | Sirmione thermal water (Lombardia, Italy), rich in sodium chloride, bromine and iodine | Chronic inflammatory and age-related illness | TNF-α, IL-1β, IL-6, IL-12; CXCL8, CCL5; ROS, antioxidant enzymes | ↓ TNF-α, IL-1β, IL-6, IL-12, CXCL8, CCL5 production ↓ ROS formation and antioxidant enzymes Sirmione water ↑ IL-10 release ↓ chronic inflammatory and age-related illness manifestations |
Vitale 2018 [34] | Bol Soc Esp Hidrol Méd | Exogenous H2S on human resting CD4 T cell polarization to Th17 and/or Treg phenotype | Differentiated ex-vivo human resting CD4 + (Th0) T cells to Th17 or Treg lineages | NaHS | Immune-mediated pathologies | CD4 T cell polarization to Th17 and/or Treg phenotype | ↑ Foxp3 mRNA levels in CD4 + T cells cultured under Treg-polarizing conditions ↑ RORγT mRNA levels in CD4 + T cells under Th17 polarizing conditions |
In vitro studies on animal samples evaluating the beneficial effects of BT on immune response in inflammatory diseases
Authors | Journal | Treatment | Experimental model | Mineral water or inorganic or organic components | Pathology | Biochemicalparameters | Results |
---|---|---|---|---|---|---|---|
Miller et al. 2012 [35] | J Biol Chem | H2S (50–500 nM) dissolved in the culture medium, for 4, 10, and 24 h | Primary mouse T lymphocytes (CD3 +), OT-II CD4 + T cells | H2S | Inflammatory processes of bowel diseases | CD69, CD25; IL-2; cystathionine γ-lyase, cystathionine β-synthase | ↑ T cell activation ↑ CD69 and IL-2 expression ↑ CD25 levels ↑ cystathionine γ-lyase and cystathionine β-synthase expression ↓ inflammatory processes |
Clinical trials and RCTs evaluating the beneficial effects of BT on immune response
First Author | Journal | N | Pathology | Age | Intervention | Treatment | Comparison | Type of water/inorganic or organic component | Systemic inflammatory Biomarkers | Stress biomarkers | Results |
---|---|---|---|---|---|---|---|---|---|---|---|
Bellometti et al. 1997 [36] | Clinica Chimica Acta | 22 | OA | 63.6 year | Mud pack treatments | 12 applications of Mature thermal mud to the whole body for 20 min at 40 °C, followed by a bath for 10–12 min at 37–38 °C | Yes (22 control group only hot bath) | Mud of Abano-Montegrotto Terme | Serum IGF-1 and TNF-α | Differences between mean values found before and after the mud pack statistically significant | |
Bellometti et al. 1998 [37] | J Investig. Med | 31 | Healthy | Mud pack Therapy | PGE2 and LTB4 | ↓ PGE2 and LTB4 in serum | |||||
Pascarelli et al. 2016 [38] | IMAJ | 103 | OA | 68.49 ± 9.0 | Mud bath therapy | 2 weeks daily local mud-packs and baths | Control group (n = 50) regular care routine (exercise, symptomatic drugs, intra-articular hyaluronic acid) | Water of the Chianciano Spa Resort (Siena, Italy) | COMP, CTX-II, MPO and hsCRP in serum | ↔ COMP, MPO and hsCRP in serum of either group ↑ in CTX-II serum levels in the mud-bath group after the treatment | |
Ortega et al. 2017 [39] | Int J Biometeorol | 21 | OA knee | 62–77 | Whole body Peloidotherapy | 1 session/die × 10 | No | SiO2, CaO, Al2O3 and Fe2O3 | IL-1β, TNF-α, IL-8, IL-6, TGF-β | SerumCortisol, eHsp72 | ↓ serum concentrations of IL-1β, TNF-α, IL-8, IL-6 and TGF-β ↑ systemic levels of cortisol ↓ circulating levels of eHsp72 |
Galvéz et al. 2018 [40] | International journal of hyperthermia | 36 | Knee OA | 70 | Whole-body mud therapy at 40–42 °C | 10-day cycle | No | SiO2, CaO, Al2O3 and Fe2O3 | IL-8, TGFb, CD4, CD 25, FOXP3, CD28, CD8, Neutrophils | ↓ circulating concentrations of IL-8 and TGF-β ↓ CD4 CD25 FOXP3 Treg cells ↑ CD8þ CD28– Treg cell ↑ neutrophils and phagocytic activity | |
Tarner et al. 2009 [41] | ClinicalRheumatology | 12 | AS | Meanage 33.4 years | Whole-body hyperthermia full bath | 9 cycles (initial water temperature of 36 °C that was increased gradually by 1 °C every 5 min to 40 °C. This temperature was maintained until the body temperature reached 38.5 °C) | Yes (12 healthy control) | nd | Serum levels of the cytokines TNF-α, IL-1B e IL-6 | ↓ TNF-α, IL-1β, and IL-6 ↔ 1 h after baseline, ↓6 h after baseline ↓At 24 h after the treatment | |
Shehata et al. 2006 [42] | The Middle European Journal of medicine | 83 | AS | 30–73 | Spa exercises therapy | 3–4 weeks spa-exercise therapy—in addition, outdoor exercises, physiotherapy, hydro-therapy and massage | Yes (control group with 10 patients with LBP and same treatment, second control group with 10 patients AS and no treatment) | Radon concentration up to 4.5 nCi/l; temperature 38–41 °C; relative humidity 70–98% | TGF-β1 | ↑ total and active TGF-β1 | |
Ardic F. 2007 [43] | Rheumatol Int | 12 | FibromyalgiaSyndrome | 43 | BT | Group 1 (n = 12) received bathing for 20 min a day, for 5 days per week for 3 week | Yes (9 group no treatment + 10 control group healthy women) | HCO3, SO4 | ESR, CRP, RF, PGE2, LTB4 and IL-1α in serum (before and at the end of general period of therapy) | ↓ serum PGE2 level ↓ IL-1 and LTB4 | |
Eysteinsdóttir et al. 2013 [44] | Scand JImmunol | 12 | Psoriasis | 36.7 | Bathing in geothermal seawater | Bathing in geothermal seawater twice daily for at least 1 h combined with NB-UVB therapy 5 days per week for 2 weeks | Yes (Of the 12 patients enrolled, six received treatment and 6 were treated with NB-UVB therapy) | Chemokines, inflammatory cytokines, T cells and TLRs in the blood and skin samples were evaluated on enrollment and at 1, 3 and 8 weeks | ↓ Th17 (IL-23R + CD4 + T cells) ↓ IL-23R expressed by these cells and their IL-17/IL-22 cytokine secretion ↓ Tc17 T cells (producing IL-17 and IL-22) after both of the treatments ↓ Th1 and Tc1 phenotype (IFN-c and TNF-α production) | ||
Yamaoka et al. 2004 [45] | J Radiat. Res | 15 | Healthy | 20–40 | A hot bathroom with a high concentration of radon | On days 1, 3, 5, 8, and 10, the inhalation of vapor from each hot spring under a condition of high humidity (about 90%) | Yes (3 groups: radon, thermal, and control.) | The temperature was 36 °C, the radon concentration was 2,080 Bq/m3 | C4 positive cells and CD8-positive cells | On days 5 and 10, ↑ CD4-positive cells ↓ CD8-positive cells in the radon group |