Inflammatory markers and depression in Parkinson's disease: a systematic review.

BACKGROUND: Parkinson's disease (PD) patients experience non-motor symptoms (NMS), which may appear before motor manifestations. The most common NMS is depression, affecting about 30-40% of PD patients. Both PD and depression are associated with an increased inflammatory burden, with studies showing elevation of diverse inflammatory markers in patients with both conditions. METHODS: A systematic review was conducted in PubMed and PsycINFO databases to investigate what inflammatory markers are associated with PD depression (PDD). Only studies in English that measured inflammatory markers and analyzed against depression scores in PD patients were included. RESULTS: A total of 1132 articles were retrieved, and 14 entries were found to be eligible. Twelve were cross-sectional studies, one was a cohort, and one was a non-randomized controlled trial. IL-17A was the only marker strongly associated with PDD, while studies assessing sIL-2R and serum amyloid A found a moderate correlation. C-reactive protein, IL-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IL-6 yielded conflicting results. Their possible roles in PDD are discussed. PDD was also related to longer disease duration and other NMS, such as anxiety, fatigue, dementia, REM sleep behavior disorder, and autonomic dysfunction. CONCLUSION: We suggest that these markers may be used for distinguishing isolated depression from that related to neurodegeneration, especially in individuals that concurrently present with other known prodromal symptoms of PD and other α-synucleinopathies. However, future prospective studies are warranted to confirm this hypothesis.

Fenton Reaction-Generated Advanced Oxidation Protein Products Induces Inflammation in Human Embryonic Kidney Cells.

Fenton reaction is a new mechanism able to generate advanced oxidation protein products (AOPPs) by exposing the human serum albumin to the Fenton system. Here, we characterized the effects of Fenton reaction-generated advanced oxidation protein products (AOPP-FR) on the gene transcription of the nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6) in human embryonic kidney cells (HEK 293). To investigate the effects of AOPP-FR and AOPP-HOCl on transcription of inflammatory genes, the NF-κB, COX-2, and IL-6 luciferase promoter activities were analyzed. AOPP-FR and AOPP-HOCl were able to induce the activation of the gene transcription of NF-κB, COX-2, and IL-6 in HEK 293 cells. However, the effects of AOPP-FR were significantly higher than the effects of AOPP-HOCl in relation to COX-2 and IL-6. AOPP-FR induces the activation of the gene transcription of NF-κB, COX-2, and IL-6 and may represent a novel pathogenic mediator of inflammation in kidney.

Iron and Oxidative Stress in Parkinson's Disease: An Observational Study of Injury Biomarkers.

Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5'-nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations observed in the pathophysiology of PD.

Lipocalina associada à gelatinase neutrofílica(NGAL) como um biomarcador de lesão renal: uma revisão / Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of kidney damage: a review

Lipocalina associada à gelatinase neutrofílica (NGAL) é uma molécula proteica predominantemente expressa na parte distal do néfron após a ocorrência de lesão renal. Diferentemente da creatinina sérica e da taxa de filtração glomerular, que são marcadores de função renal, os níveis aumentados de NGAL, tanto no soro quanto na urina, estão intimamente ligados a lesões estruturais do néfron.Os estudos clínicos indicam que poucas horas após a ocorrência da lesão renal aguda os níveis séricos e urinários de NGAL já se apresentam significativamente elevados, enquanto os níveis séricos de creatinina e a sua depuração renal apenas sofrem alterações significativas entre 24-48hapós a lesão. Assim, a utilização de marcadores de função renal, usualmente avaliados na práticaclínica, pode apresentar algumas limitações além de dificultar a aplicação de medidas precoces quevisam a proteção renal. Esta revisão da literatura tem por objetivo analisar os aspectos biológicos e as aplicações da mensuração de NGAL em algumas condições clínicas, incluindo injúria renal, nefropatias e isquemia renal.

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein molecule predominantly expressed in the distal part of the nephron following the occurrence of renal damage. Differently from serum creatinine and glomerular filtration rate, which are markers of renal function, increased levels of NGAL in both serum and urine are closely linked to structural damage of the nephron. Clinical studies indicate that within a few hours of occurrence Of acute renal injury serum and urinary NGAL levels are already significantly elevated, while serum creatinine levels and renal clearance only change significantly between 24-48 hours after injury. Thus, the use of renal function markers, usually evaluated in practice, may present some limitations, as well as hinder the application of early measures that aim at renal protection. This review of the literature aims to analyze the biological aspects and applications of NGAL measurement in some clinical conditions, including renal injury, nephropathy and renal ischemia.

Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of kidney damage: a review / Lipocalina associada à gelatinase neutrofílica (NGAL) como um biomarcador de lesão renal: uma revisão

Neutrophil gelatinase- associated lipocalin (NGAL) is a protein molecule predominantly expressed in the distal nephron after the occurrence of renal injury. Unlike the serum creatinine and the glomerular filtration rate, which are the renal function markers, the increased levels of NGAL, both in serum and urine, are closely linked to the structural injury to the nephron. Clinical studies indicate that a few hours after the occurrence of acute renal injury, the serum and urinary levels of NGAL are already significantly elevated, while the serum creatinine levels and renal clearance only undergo significant changes between 24-48h after injury. Thus, the use of renal function markers, usually assessed in the clinical practice, they may have some limitations also hindering the implementation of early measures aimed at protecting the kidneys. This literature review aims at examining the biological aspects and the applications of NGAL measurement in some clinical conditions, including kidney failure, kidney diseases and renal ischemia.

Lipocalina associada à gelatinase neutrofílica (NGAL) é uma molécula proteica predominantemente expressa na parte distal do néfron após a ocorrência de lesão renal. Diferentemente da creatinina sérica e da taxa de filtração glomerular, que são marcadores de função renal, os níveis aumentados de NGAL, tanto no soro quanto na urina, estão intimamente ligados a lesões estruturais do néfron. Os estudos clínicos indicam que poucas horas após a ocorrência da lesão renal aguda os níveis séricos e urinários de NGAL já se apresentam significativamente elevados, enquanto os níveis séricos de creatinina e a sua depuração renal apenas sofrem alterações significativas entre 24-48h após a lesão. Assim, a utilização de marcadores de função renal, usualmente avaliados na prática clínica, pode apresentar algumas limitações além de dificultar a aplicação de medidas precoces que visam a proteção renal. Esta revisão da literatura tem por objetivo analisar os aspectos biológicos e as aplicações da mensuração de NGAL em algumas condições clínicas, incluindo injúria renal, nefropatias e isquemia renal.

Circulating Double-Stranded DNA in Plasma of Hemodialysis Patients and its Association with Iron Stores.

BACKGROUND: Chronic kidney disease (CKD) is characterized by oxidative stress, and most of the adverse effects of CKD are mediated by iron-catalyzed ROS generation. The DNA, in particular, is more susceptible to attack by ROS than other proteins and membrane lipids. Considering the evidence on the relationship between CKD, iron metabolism, and DNA damage, the purpose of this study was to evaluate cell-free DNA in the plasma of HD patients and its association with iron status biomarkers and kidney function. METHODS: Measurements of the circulating cell-free DNA in plasma, iron, ferritin, transferrin and other biochemical parameters were performed in 40 chronic hemodialysis (HD) patients and 40 healthy controls. Blood samples were also collected 1 hour before and 1 hour after the HD session to check whether a single HD session would be able to promote an increase in cell-free DNA in the plasma. RESULTS: Cell-free DNA in plasma was significantly increased in HD patients in comparison with healthy controls (p = 0.0017), and significant correlations were observed between cell-free DNA and GFR and ferritin. Our findings showed that a single HD session was not able to promote an increase in cell-free DNA. It was reported that increased ferritin levels and reduced GFR were associated with higher circulating cell-free DNA. CONCLUSIONS: The HD patients presented increased ceIl-free DNA. In addition, the increase of ferritin levels and the decrease of GFR were associated with DNA damage. We also observed that a single HD session was not able to promote an increase in cell-free DNA.

Apoptotic markers and DNA damage are related to late phase of stroke: Involvement of dyslipidemia and inflammation.

Oxidative stress and brain inflammation are thought to contribute to the pathophysiology of cerebral injury in acute stroke, leading to apoptosis and cell death. Lipid accumulation may lead to progression of carotid plaques and inflammation, contributing to increased acute stroke risk. However, little is known about these events and markers in the late stroke (>6 months) and if dyslipidemia could contribute to disease's pathophysiology in a later phase. In this case-control study, we recruited patients in the late stroke phase (n=40) and health subjects (control group; n = 40). Dichlorodihydrofluorescein (DCFH), nitrite/nitrate (NOx), Tumor necrosis factor-alpha (TNF-α), Acetylcholinesterase (AChE), Caspase 8 (CASP 8), Caspase 3 (CASP 3) and Picogreen (PG) were measured in periphery blood samples. Furthermore, a correlation among all measured markers (DCFH, NOx, TNF-α, AChE, CASP 8, CASP 3 and PG) was realized. The marker levels were also compared to triglycerides (TG), total (CHO), LDL and HDL cholesterol levels and medications used. Statistical analyses showed that stroke patients presented an increase of DCFH, NOx, TNF-α and AChE levels when compared to control subjects. In addition, we observed that stroke patients had significantly higher CASP 8, CASP 3 and PG levels than control group. A significant correlation between TNF-α with CASP 8 (r = 0.4) and CASP 3 (r = 0.4) levels was observed, but not with oxidative/nitrosative markers. Moreover, we observed that stroke patients with dyslipidemia had significantly higher TNF-α, CASP 8 and CASP 3 levels than stroke without dyslipidemia and control groups. Our findings suggest that oxidative and inflammatory markers may be still increased and lead to caspase activation and DNA damage even after 6 months to cerebral injury. Furthermore, it is plausible to propose that dyslipidemia may contribute to worsen proinflammatory state in a later phase of stroke and an increased risk to new neurovascular events.

Association between hypertriglyceridemia and protein oxidation and proinflammatory markers in normocholesterolemic and hypercholesterolemic individuals.

BACKGROUND: Although hypercholesterolemia is a well-established risk factor for coronary heart disease, evidence suggests that increased triglyceride (TG) concentrations are also an independent risk factor. TG concentrations >150mg/dl are observed nearly twice as often in subjects with atherosclerosis. We assessed the association between hypertriglyceridemia and protein oxidation and proinflammatory markers in normocholesterolemic and hypercholesterolemic individuals. METHODS: We included 127 volunteers enrolled in Cruz Alta, RS, Brazil. The patients were stratified based on total cholesterol and TG concentrations for analysis of associations with inflammation (high-sensitivity C-reactive protein - hs-CRP), endothelial dysfunction (nitric oxide - NOx) and oxidative stress (advanced oxidation protein products - AOPPs; ischemia-modified albumin - IMA). Correlations between variables were determined and multiple regression analysis was employed to investigate whether some variables correlate with TG concentrations. RESULTS: Hypertriglyceridemia was related to oxidative stress and proinflammatory markers in individuals independent of total cholesterol concentrations. Moreover, the results indicate a stronger association of tested biomarkers with TG concentrations than with total cholesterol. The results indicate a positive correlation between oxidative stress and TG concentrations in the sera of hypercholesterolemia subjects. AOPPs and IMA concentrations were associated with the presence of hypertriglyceridemia in a manner that was independent of age, gender, hypertension and diabetes mellitus disease, smoking habits, sedentary lifestyle, BMI, waist circumference, LDL, HDL and total cholesterol concentrations. CONCLUSIONS: We speculate that TG concentrations can reflect the enhancement of protein oxidation and proinflammation.

An alternative pathway through the Fenton reaction for the formation of advanced oxidation protein products, a new class of inflammatory mediators.

The accumulation of advanced oxidation protein products (AOPPs) has been linked to several pathological conditions, and their levels are formed during oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants produced by myeloperoxidase (MPO). However, it was suggested that the generation of this mediator of inflammation may also occur via an MPO-independent pathway. The aim of this study was to induce the formation of AOPPs in vitro through Fenton reaction and to investigate whether this generation could be counteracted by N-acetylcysteine (NAC) and fructose-1,6-bisphosphate (FBP). The complete Fenton system increased the AOPPs levels and both NAC and FBP were capable of inhibiting the formation of Fenton reaction-induced AOPPs. These data provide a new hypothesis about another pathway of AOPPs formation, as well as report that NAC and FBP may be good candidates to neutralize pro-inflammatory and pro-oxidant effects of AOPPs in several diseases.

Ischemia-modified albumin and inflammatory biomarkers in patients with prostate cancer.

BACKGROUND: Prostate cancer has become a public health problem in many countries and there is evidence which indicates that inflammation and oxidative stress play a key role in the pathogenesis of this disease. Thus, the aim of this study was to evaluate the concentrations of new biomarkers of oxidative stress, ischemia-modified albumin (IMA) and ferric reducing ability of plasma (FRAP), as well as the inflammatory markers in patients with prostate cancer. METHODS: CRP, IMA, FRAP, fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, uric acid, creatinine, albumin, AST, ALT, ADA, total PSA (tPSA), free PSA, and proportion of free PSA (fPSA%) were measured in 25 patients with prostate cancer and in 30 healthy subjects. RESULTS: tPSA, CRP, and IMA were significantly higher in patients with prostate cancer. In contrast, fPSA% and FRAP were significantly lower in these patients. However, no significant differences were observed when IMA values were adjusted for serum albumin. Significant correlations were also observed for tPSA and CRP (r = 0.5104, p < 0.001) and for fPSA% and CRP (r = -0.5059, p < 0.001). CONCLUSIONS: We demonstrated that both inflammatory and oxidative processes are increased during prostate cancer and also that there is a reduction of antioxidant defenses in this pathology.

Assessment of inflammatory and oxidative biomarkers in obesity and their associations with body mass index.

The aim of this study was to evaluate the inflammatory and oxidative biomarkers' levels in obese subjects and their associations with body mass index (BMI), in order to investigate the role of these biomarkers in obesity. Fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, apolipoprotein A, apolipoprotein B, albumin, urinary albumin, creatinine, glomerular filtration rate, interleukin-6 (IL-6), nitrate/nitrite (NOx), and ischemia-modified albumin (IMA) were measured in 93 subjects divided according to different BMI. IL-6, urinary albumin, and IMA levels were significantly higher in obese subjects. However, the levels of NOx were significantly lower in this population. Significant correlations between BMI and IL-6 (r = 0.326, P = 0.002), NOx (r = -0.249, P = 0.021), urinary albumin (r = 0.270, P = 0.008), and IMA (r = 0.286, P = 0.005) were reported. We have shown an increase of IL-6, urinary albumin, and IMA combined with lower levels of NOx in obese patients and an association between of these biomarkers with BMI, suggesting a possible interplay of oxidative stress, inflammation, and endothelial dysfunction state in obesity.

Fructose-1,6-bisphosphate and N-acetylcysteine attenuate the formation of advanced oxidation protein products, a new class of inflammatory mediators, in vitro.

The accumulation of advanced oxidation protein products (AOPP) has been linked to several pathological conditions. Previous studies have identified AOPP as a novel biomarker of oxidative damage to proteins and a novel class of mediator of inflammation. The aim of this study was to determine the effects of fructose-1,6-bisphosphate (FBP) and N-acetylcysteine (NAC) as well as the synergistic effect of both treatments on the formation of AOPP in vitro. For this purpose, we incubated the human serum albumin (HSA) with various hypochlorous acid (HOCl) concentrations to produce albumin-advanced oxidation protein products (HSA-AOPP). Both FBP and NAC were capable of inhibiting the formation of HOCl-induced AOPP in a concentration-dependent manner. The synergistic effect promoted by the association of these drugs showed to be more effective than when tested alone. Thus, both FBP and NAC may be good candidates to mitigate and neutralize pro-inflammatory and pro-oxidant effects of AOPP in several diseases.

Hippocampal PKA/CREB pathway is involved in the improvement of memory induced by spermidine in rats.

Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-D-aspartate (NMDA) receptor function, and has been reported to facilitate memory formation. In the current study we determined whether or not the PKA/CREB signaling pathway is involved in SPD-induced facilitation of memory of inhibitory avoidance task in adult rats. The post-training administration of the cAMP-dependent protein kinase (PKA) inhibitor, N-[2-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide [H-89, 0.5 ρmol intrahippocampal (ih)] or the antagonist of the NMDA receptor polyamine-binding site (arcaine, 0.02 nmol ih) with SPD (0.2 nmol ih) prevented memory improvement induced by SPD. Intrahippocampal administration of SPD (0.2 nmol) facilitated PKA and cAMP response element-binding protein (CREB) phosphorylation in the hippocampus 180 min, but not 30 min, after administration, and increased translocation of the catalytic subunit of PKA into the nucleus. Arcaine (0.02 nmol) and H-89 (0.5 ρmol) prevented the stimulatory effect of SPD on PKA and CREB phosphorylation. These results suggest that memory enhancement induced by the ih administration of SPD involves the PKA/CREB pathways in rats.

Influência dos anticoagulantes e da temperatura de armazenamento sobre os níveis sanguíneos de nitrito / Effects of anticoagulants and storage temperature on blood nitrite levels

A mensuração dos metabólitos do óxido nítrico pode ser útil para a melhor compreensão de diferentes processos fisiopatológicos. Este estudo avaliou a influência de diferentes anticoagulantes (ácido etilenodiaminotetracético [EDTA], citrato e heparina) e do armazenamento a -20ºC por quatro meses sobre os níveis de nitrito, sendo estes mensurados em amostras de soro e plasma pelo método de Griess. Os tipos de amostra utilizados (soro ou plasma) e de anticoagulante usado na coleta não influenciaram significativamente os níveis de nitrito, independentemente de as dosagens serem realizadas em amostras frescas ou naquelas mantidas a -20ºC por quatro meses.

The measurement of nitric oxide metabolites may be useful for better understanding of different physiopathological processes. Thus, the aim of this study was to evaluate the influence of different anticoagulants (EDTA, citrate and heparin) and four-month storage at -20ºC on nitrite levels. The serum and plasma samples were analyzed by using the Griess method. The type of sample (serum or plasma) or anticoagulant used in the collection did not influence on nitrite levels significantly, regardless the fact they were fresh or four-month samples stored at -20ºC.