No abstract

The latest studies have indicated a strong relationship between systemic insulin resistance (IR) and higher incidence of neurodegeneration, dementia, and mild cognitive impairment. Although some of these abnormalities could be explained by chronic hyperglycaemia, hyperinsulinemia, dyslipidaemia, and/or prolonged whole-body inflammation, the key role is attributed to the neuronal redox imbalance and oxidative damage. In this mini review, we provide a schematic overview of intracellular oxidative stress and mitochondrial abnormalities in the IR brain. We highlight important correlations found so far between brain oxidative stress, ceramide generation, β-amyloid accumulation, as well as neuronal apoptosis in the IR conditions.

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.

Despite the proven role of oxidative stress in numerous systemic diseases and in the process of aging, little is still known about the salivary redox balance of healthy children, adults, and the elderly. Our study was the first to assess the antioxidant barrier, redox status, and oxidative damage in nonstimulated (NWS) and stimulated (SWS) saliva as well as blood samples of healthy individuals at different ages. We divided 90 generally healthy people into three equally numbered groups based on age: 2–14 (children and adolescents), 25–45 (adults), and 65–85 (elderly people). Antioxidant enzymes (salivary peroxidase (Px), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase-1 (SOD)), nonenzymatic antioxidants (reduced glutathione (GSH) and uric acid (UA)), redox status (total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI)), and oxidative damage products (advanced glycation end products (AGE), advanced oxidation protein products (AOPP), and malondialdehyde (MDA)) were evaluated in NWS and SWS as well as in erythrocyte/plasma samples. We demonstrated that salivary and blood antioxidant defense is most effective in people aged 25–45. In the elderly, we observed a progressive decrease in the efficiency of central antioxidant systems (↓GPx, ↓SOD, ↓GSH, and ↓TAC in erythrocytes and plasma vs. adults) as well as in NWS (↓Px, ↓UA, and ↓TAC vs. adults) and SWS (↓TAC vs. adults). Both local and systemic antioxidant systems were less efficient in children and adolescents than in the group of middle-aged people, which indicates age-related immaturity of antioxidant mechanisms. Oxidative damage to proteins (↑AGE, ↑AOPP) and lipids (↑MDA) was significantly higher in saliva and plasma of elderly people in comparison with adults and children/adolescents. Of all the evaluated biomarkers, only salivary oxidative damage products generally reflected their content in blood plasma. The level of salivary redox biomarkers did not vary based on gender.

There are still missing non-invasive biomarkers of chronic kidney disease (CKD) in children. Therefore, the aim of the study was to evaluate oxidative stress indicators in the non-stimulated (NWS) and stimulated saliva (SWS) of CKD children (n = 25) and healthy controls (n = 25). Salivary antioxidants (catalase (CAT), peroxidase (Px), superoxide dismutase (SOD), uric acid (UA), reduced glutathione (GSH), albumin), redox status (total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI)), and oxidative damage products (advanced glycation end products (AGE), advanced oxidation protein products (AOPP), malondialdehyde (MDA)) were evaluated. We have demonstrated the significantly higher activity of SWS GPx and SOD, as well as elevated concentrations of UA and albumin in NWS and SWS of CKD children vs. the control group. TAC, TOS and OSI were significantly higher only in SWS, while oxidative damage products (AGE, AOPP and MDA) were significantly higher in both NWS and SWS of CKD children. ROC analysis showed a considerably high diagnostic value of AOPP in both NWS and SWS of CKD children compared to controls (AUC = 0.92; 0.98). CKD is responsible for disturbances in salivary antioxidant systems and oxidative damage to proteins and lipids. Salivary AOPP can be a potential biomarker of CKD in children.

Still little is known about the role of oxidative stress (OS) in the pathogenesis of the salivary gland dysfunction in the course of insulin resistance (IR). To induce IR rats was fed with a high fat diet (HFD) during 8 weeks. Stimulated and non-stimulated salivary flow rate, total protein, as well as oxidative damage markers: 4-HNE protein adduct, 8-isoprostanes (8-isoP), 8-hydroxy-D-guanosine (8-OHdG), advanced oxidation protein product (AOPP), and protein carbonyls (PC) were determined in the plasma and submandibular and parotid glands of IR and control rats. We have shown a significant decrease (45%) of the stimulated salivary flow rate, and in the total protein concentration in the parotid (35%) and submandibular (10%) glands of HFD IR as compared to the control rats. The level of 4-HNE protein adduct (15%) and 8-isoP (20%) in the submandibular glands of IR rats as well as total level of 4-HNE protein adduct (39%), 8-isoP (27%), AOPP (25%), PC (32%), and 8-OHdG (18%) in the parotid glands of IR rats were significantly higher as compared to the control group. We showed no correlation between the assessed OS parameters in the plasma and salivary glands. However, the redox balance in both glands shifted toward the oxidative status, parotid glands of IR rats are exposed to greater intensity OS. Stimulated secretory ability and mechanisms involved in the synthesis/secretion of proteins in the salivary glands are depressed in the course of IR. Oxidative damage in the salivary glands arises independently from the general OS in the course of insulin resistance induced by a high fat diet.

Oxidative stress is a key pathogenic factor in both neurogenerative and metabolic diseases. However, its contribution in the brain complications of insulin resistance is still not well understood. Therefore, the aim of this study was the evaluation of redox homeostasis and oxidative damage in the hypothalamus and cerebral cortex of insulin-resistant and control rats. 16 male Wistar rats were divided into two equal groups (n = 8): the control and high fat diet group (HFD). Prooxidant enzymes (xanthine oxidase and NADPH oxidase); enzymatic and nonenzymatic antioxidants [glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase-1 (SOD-1), and uric acid (UA)]; and oxidative damage products [advanced glycation end products (AGE), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG)] as well as the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and total ferric reducing ability of sample (FRAP) were evaluated in the hypothalamus and cerebral cortex as well as serum/plasma of HFD-fed and control rats. The activity of prooxidant enzymes was significantly increased in the cerebral cortex and hypothalamus of HFD-fed rats vs. control rats. Additionally, we have showed enhanced antioxidant efficiency in the hypothalamus (↑CAT, ↑UA, ↑TAC, and ↑FRAP) and cerebral cortex (↑GPx, ↑CAT, ↑SOD-1, ↑UA, ↑TAC, and ↑FRAP) of HFD-fed rats. All of the oxidative damage markers (AGE, 4-HNE, MDA, 8-OHdG, and OSI) were significantly increased in the cerebral cortex of insulin-resistant rats, while only 4-HNE and MDA were markedly higher in the hypothalamus of the HFD group. Summarizing, the results of our study indicate an adaptive brain response to the increased production of free radicals under insulin resistance conditions. Despite the increase in antioxidative defense systems, this mechanism does not protect both brain structures from oxidative damages. However, the cerebral cortex is more susceptible to oxidative stress caused by HFD.

Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.