Could inflammation contribute to salivary gland dysfunction in patients with chronic heart failure?

Heart failure (HF) is one of the leading causes of death worldwide. HF results not only in cardiovascular dysfunction, but also numerous pathologies in the oral cavity and salivary glands. The present study is the first to evaluate whether salivary inflammatory and anti-inflammatory factors may be related with the occurrence of hyposalivation in HF patients. We also evaluated the potential of salivary biomarkers in the diagnostics of HF. The study included 30 women with HF and 30 sex- and age-matched healthy controls. We demonstrated significantly higher levels of pro-inflammatory cytokines, anti-inflammatory cytokines, Th1, Th2, Th17, chemokines and growth factors in unstimulated saliva of HF patients compared to controls. However, the results do not indicate dominance of either branch of the immune response. The concentration of selected biomarkers is significantly higher in patients with HF and salivary gland dysfunction compared to patients with normal saliva secretion and healthy subjects (IL-1ß, TNF-α, IL-7, IL-13, INF-γ, IL-12, IL-15, IL-5, IL-6, IL-9, IL-17, MCP-1/CCL-2, EOTAXIN/CCL11, RANTES/CCL5, GM-CSF, VEGF, FGF basic, PDFG-BB). Multivariate regression analysis showed that the content of salivary cytokines, chemokines and growth factors is highly dependent on salivary gland function, i.e. salivary flow rate, total protein content and amylase activity. Using receiver operating characteristic (ROC) analysis, we showed that salivary TNF-α, INF-γ, IL-12 and EOTAXIN/CCL11 differentiated patients with HF and hyposalivation with the highest sensitivity and specificity compared to patients with normal salivary secretion and controls. Interestingly, the content of some pro- and anti-inflammatory mediators in saliva significantly exceeds their concentration in plasma. In addition, salivary biomarker levels do not reflect their plasma content, which may suggest a different nature/severity of inflammatory changes at the central (blood) and local (salivary) levels. Although our study was purely observational, the significantly higher concentration of inflammatory parameters in saliva compared to plasma, as well as the lack of saliva-blood correlation, may suggest increased production/secretion of these compounds in salivary cells of HF patients. ROC analysis did not confirm the diagnostic utility of salivary cytokines and chemokines in the differential diagnosis of HF patients.

Salivary gland dysfunction and salivary redox imbalance in patients with Alzheimer's disease.

Alzheimer's disease (AD) is associated with the deposition of ß-amyloid in the brain. AD accounts for over 50% of cases of dementia which results from disturbances in redox homeostasis. Indeed, increased intensity of protein oxidation and nitration as well as lipid peroxidation is observed in brain areas with considerable amounts of amyloid plaques and neurofibrillary tangles. However, little is known about the oxidoreductive balance of salivary glands in AD patients. Therefore, the aim of this study was to evaluate the antioxidant barrier and oxidative/nitrosative stress biomarkers in stimulated saliva and blood of AD patients. The study was participated by 25 AD patients and 25 non-demented controls without neurological diseases or cognitive impairment, matched by age and gender to the study group. The number of patients was determined based on a previous pilot study (test power = 0.9). We found a significant decrease in the activity of erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx), increased activity of catalase (CAT) and reduced concentration of plasma non-enzymatic antioxidants (uric acid, UA and reduced glutathione, GSH). In contrast, in the stimulated saliva of AD patients we observed significantly decreased activity of all antioxidant enzymes (SOD, CAT and GPx) as well as concentration of GSH compared to the control group. The content of lipid (malondialdehyde, MDA) and protein (advanced oxidation protein products, AOPP; advanced glycation end-products, AGE) oxidation products as well as biomarkers of nitrosative stress (peroxynitrite, nitrotyrosine) was significantly higher in both saliva and plasma of AD patients compared to the controls. In AD patients, we also observed a considerable decrease in stimulated saliva secretion and salivary total protein content, and an increase in salivary ß-amyloid concentration. In conclusion, AD results in redox imbalance towards oxidative reactions, both at the level of the oral cavity and the entire body. General redox balance disturbances do not coincide with salivary redox balance disturbances. Reduction in stimulated saliva secretion in AD patients reflects secretory dysfunction of the parotid glands.

Salivary Gland Dysfunction in Patients with Chronic Heart Failure Is Aggravated by Nitrosative Stress, as Well as Oxidation and Glycation of Proteins.

Chronic heart failure (HF) is an important clinical, social, and economic problem. A key role in HF progression is played by oxidative stress. Free oxygen radicals, formed under the conditions of hypoxia and reperfusion, participate in myocardial stunning and other forms of post-reperfusion damage. HF patients also suffer from disorders connected with saliva secretion. However, still little is known about the mechanisms that impair the secretory function of salivary glands in these patients. In the presented study, we were the first to compare the antioxidant barrier, protein glycoxidation, and nitrosative/nitrative stress in non-stimulated (non-stimulated whole saliva (NWS)) and stimulated (SWS) saliva of HF patients. The study included 50 HF patients with normal saliva (NS) secretion (n = 27) and hyposalivation (HS) (n = 23), as well as an age- and gender-matched control group (n = 50). We demonstrated that, in NWS of HF patients with HS, the concentration of low-molecular-weight non-enzymatic antioxidants decreased (↓total polyphenols, ↓ascorbic acid, ↓reduced glutathione, ↓albumin) compared to HF patients with normal saliva (NS) secretion, as well as the control group (except albumin). We also observed increased content of protein glycoxidation products (↑dityrosine, ↑kynurenine, ↑glycophore) in NWS and SWS of HF patients with HS compared to healthy controls. Interestingly, the content of dityrosine, N-formylkynurenine, and glycophore in NWS was also significantly higher in HF patients with HS compared to those with NS secretion. The concentration of NO was considerably lower, while the levels of peroxynitrite and nitrotyrosine were significantly higher in NWS and SWS of HF subjects with HS compared to the controls. Salivary gland dysfunction occurs in patients with chronic HF with the submandibular salivary glands being the least efficient. Oxidative/nitrosative stress may be one of the mechanisms responsible for the impairment of salivary gland secretory function in HF patients.

Enhanced Inflammation and Nitrosative Stress in the Saliva and Plasma of Patients with Plaque Psoriasis.

Psoriasis is the most common inflammatory skin disease, characterized by the release ofproinflammatory cytokines from lymphocytes, keratinocytes, and dendritic cells. Although psoriasis is considered an immune-mediated inflammatory disease, its effect on secretory activity of salivary glands and quantitative composition of saliva is still unknown. The aim of this study was to evaluate the secretion of saliva as well as several selected inflammation and nitrosative stress biomarkers in unstimulated and stimulated saliva as well as plasma of psoriasis patients. We demonstrated that, with progressing severity and duration of the disease, the  secretory function of the parotid and submandibular salivary glands is lost, which is  manifested as decreased unstimulated and stimulated saliva secretion and reduced salivary amylase activity and total protein concentration. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and interferon-gamma (INF-α) were significantly higher, whereas interleukin-10 (IL-10) content was considerably lower in unstimulated and stimulated saliva of patients with psoriasis compared to the controls, and the changes increased with the disease duration. Similarly, we observed that the intensity of nitrosative stress in the salivary glands of psoriasis patients depended on the duration of the disease. By means of receiver operating characteristic (ROC) analysis, we showed that the evaluation of nitric oxide (NO), nitrotyrosine, and IL-2 concentration in non-stimulated saliva with high sensitivity and specificity differentiatedpsoriasis patients on the basis of the rate of saliva secretion (normal salivation vs. hyposalivation). In summary, the dysfunction of salivary glands in psoriasis patients is caused by inflammation and nitrosative stress.

Salivary Oxidative Stress Increases With the Progression of Chronic Heart Failure.

The aim of the study was to evaluate the rate of reactive oxygen species (ROS) production, antioxidant barrier, and oxidative damage in non-stimulated (NWS) and stimulated (SWS) saliva as well as plasma/erythrocytes of 50 patients with chronic heart failure (HF) divided into the two subgroups: NYHA II (33 patients) and NYHA III (17 patients). The activity of superoxide dismutase and catalase was statistically increased in NWS of HF patients as compared to healthy controls. The free radical formation, total oxidant status, level of uric acid, advanced glycation end products (AGE), advanced oxidation protein products and malondialdehyde was significantly elevated in NWS, SWS, and plasma of NYHA III patients as compared to NYHA II and controls. We were the first to demonstrate that with the progression of HF, disturbances of enzymatic and non-enzymatic antioxidant defense, and oxidative damage to proteins and lipids occur at both central (plasma/erythrocytes) and local (saliva) levels. In the study group, we also observed a decrease in saliva secretion, total salivary protein and salivary amylase activity compared to age- and gender-matched control group, which indicates secretory dysfunction of salivary glands in patients with HF. Salivary AGE may be a potential biomarker in differential diagnosis of HF.

Salivary Redox Biomarkers in Different Stages of Dementia Severity.

This study is the first to evaluate oxidative stress biomarkers in saliva/blood of patients with varying degrees of dementia progression. The study included 50 healthy controls and 50 dementia patients divided into two groups: those with mild and moderate dementia (MMSE 11-23) and patients suffering from severe dementia (MMSE 0-10). Cognitive functions of the subjects were assessed using the Mini Mental State Examination (MMSE). Enzymatic and non-enzymatic antioxidants, oxidative damage products and protein glycoxidative modifications were determined in non-stimulated (NWS) and stimulated (SWS) saliva as well as erythrocyte/plasma samples. Generally, in dementia patients, we observed the depletion of antioxidant defences leading to oxidative and glycoxidative damage in NWS, SWS and blood samples. Both salivary and blood oxidative stress increased with the severity of the disease, and correlated with a decrease of cognitive functions. Interestingly, in dementia patients, reduced glutathione (GSH) in NWS correlated not only with the severity of dementia, but also with GSH concentration in the plasma. In receiver operating characteristic (ROC) analysis, we have demonstrated that salivary GSH clearly distinguishes patients with severe dementia from those suffering from mild or moderate dementia (area under the curve (AUC) = 1). Therefore, salivary GSH can be used as a non-invasive biomarker of cognitive impairment.

Antioxidant Defence, Oxidative Stress and Oxidative Damage in Saliva, Plasma and Erythrocytes of Dementia Patients. Can Salivary AGE be a Marker of Dementia?

Oxidative stress plays a crucial role in dementia pathogenesis; however, its impact on salivary secretion and salivary qualities is still unknown. This study included 80 patients with moderate dementia and 80 healthy age- and sex-matched individuals. Salivary flow, antioxidants (salivary peroxidase, catalase, superoxide dismutase, uric acid and total antioxidant capacity), and oxidative damage products (advanced oxidation protein products, advanced glycation end products (AGE), 8-isoprostanes, 8-hydroxy-2'-deoxyguanosine and total oxidant status) were estimated in non-stimulated and stimulated saliva, as well as in plasma and erythrocytes. We show that in dementia patients the concentration/activity of major salivary antioxidants changes, and the level of oxidative damage to DNA, proteins and lipids is increased compared to healthy controls. Non-stimulated and stimulated salivary secretions were significantly reduced in dementia patients. The deterioration in mini mental state examination (MMSE) score correlated with salivary AGE levels, which when considered with receiver operating characteristic (ROC) analysis, suggests their potential role in the non-invasive diagnosis of dementia. In conclusion, dementia is associated with disturbed salivary redox homeostasis and impaired secretory function of the salivary glands. Salivary AGE may be useful in the diagnosis of dementia.

Oxidative Modification of Biomolecules in the Nonstimulated and Stimulated Saliva of Patients with Morbid Obesity Treated with Bariatric Surgery.

Morbid obesity leads to progressive failure of many human organs and systems; however, the role of oxidative damage to salivary composition is still unknown in the obese patients. In this study, we assessed the effect of bariatric surgery on oxidative damage in nonstimulated (NS) and stimulated (S) whole saliva. The study included 47 subjects with morbid obesity as well as 47 age- and gender-matched healthy volunteers. Oxidative modifications to lipids (4-hydroxynonenal (4-HNE) and 8-isoprostanes (8-isoP)), proteins (advanced oxidation protein products (AOPP) and protein carbonyl groups (PC)), and DNA (8-hydroxy-D-guanosine (8-OHdG)) were analyzed in morbidly obese patients before and after bariatric surgery as well as in the healthy controls. The concentrations of 8-isoP, AOPP, PC, and 8-OHdG were significantly higher in both NS and S of patients with morbid obesity than in the control patients and compared to the results obtained 6 months after bariatric surgery. The levels of oxidative damage markers were also higher in S versus NS of morbidly obese patients. In summary, morbid obesity is associated with oxidative damage to salivary proteins, lipids, and DNA, while bariatric treatment generally lowers the levels of salivary oxidative damage.

Lysosomal Exoglycosidase Profile and Secretory Function in the Salivary Glands of Rats with Streptozotocin-Induced Diabetes.

Before this study, there had been no research evaluating the relationship between a lysosomal exoglycosidase profile and secretory function in the salivary glands of rats with streptozotocin- (STZ-) induced type 1 diabetes. In our work, rats were divided into 4 groups of 8 animals each: control groups (C2, C4) and diabetic groups (STZ2, STZ4). The secretory function of salivary glands-nonstimulated and stimulated salivary flow, α-amylase, total protein-and salivary exoglycosidase activities-N-acetyl-ß-hexosaminidase (HEX, HEX A, and HEX B), ß-glucuronidase, α-fucosidase, ß-galactosidase, and α-mannosidase-was estimated both in the parotid and submandibular glands of STZ-diabetic and control rats. The study has demonstrated that the activity of most salivary exoglycosidases is significantly higher in the parotid and submandibular glands of STZ-diabetic rats as compared to the healthy controls and that it increases as the disease progresses. Reduced secretory function of diabetic salivary glands was also observed. A significant inverse correlation between HEX B, α-amylase activity, and stimulated salivary flow in diabetic parotid gland has also been shown. Summarizing, STZ-induced diabetes leads to a change in the lysosomal exoglycosidase profile and reduced function of the salivary glands.

Antioxidant profile, carbonyl and lipid oxidation markers in the parotid and submandibular glands of rats in different periods of streptozotocin induced diabetes.

OBJECTIVE: The aim of this study was to estimate the antioxidants barrier, and the oxidative stress in the salivary glands of rats in different periods of streptozotocin induced diabetes. DESIGN: Rats were divided in: 4 control (C2/4/10/14) and 4 experimental (DM2/4/10/14) groups. Salivary glands were removed 2/4/10/14 weeks after streptozotocin injection. Peroxidase (Px), uric acid (UA), total antioxidant status (TAS), superoxide dismutases (SODs), catalase (CAT), malonylodialdehyde (MDA), advanced glycation end products (AGE) concentrations were examined. RESULTS: TAS, Px were lower in the parotid diabetic glands throughout the whole experiment. TAS in the submandibular diabetic glands was lower in 2nd and 4th and higher in 14th week. Px in the submandibular diabetic glands was reduced in 4th and increased in 14th week. UA was lower in parotid, elevated in submandibular diabetic glands in 4th, 10th, 14th weeks. In the submandibular as compared to parotid glands an increase in TAS and UA was observed in 10th and 14th, Px in 14th week. In all periods, a significant increase in AGE was observed in both diabetic salivary glands. An increase in MDA was observed in the parotid diabetic glands in the 4th, 10th, 14th of the study. In the submandibular glands this increase was observed in the 2nd, 4th, 10th week, in the 14th week, the MDA level was significantly reduced in comparison to the control. CONCLUSION: The antioxidants of parotid glands are deficient throughout the whole experiment. In the last period submandibular glands copy with free radicals, becoming the main antioxidant's source.

Salivary antioxidants in patients with systemic sclerosis.

BACKGROUND: In spite of relatively large amount of evidence that oxidative stress is implicated in the pathogenesis of systemic sclerosis, there is no study analyzing antioxidants profile of the saliva of these patients. The aim of this study was to compare salivary antioxidants in subjects with systemic sclerosis and the healthy controls. METHODS: The unstimulated and stimulated salivary flow and the specific activity of peroxidase, superoxide dismutase 1, the total amount of uric acid, and total antioxidant status were determined in two subgroups of systemic sclerosis women and healthy controls. RESULTS: A significant increase in the specific activity of peroxidase, a significant decrease in the total amount of uric acid and total antioxidants status in unstimulated saliva as well as a significant increase in all antioxidants examined in stimulated saliva of group with normal salivary flow rate as compared to the healthy controls were observed. Our results showed a significant decrease in the specific activity of peroxidase in unstimulated and a significant decrease in all antioxidants examined in stimulated saliva of the group with hyposalivation as compared to the group with normal salivary flow rate. CONCLUSIONS: Our results prove that impairment of the salivary glands in the course of systemic sclerosis may be attributed to free radicals, and it is correlated with disease duration.