Increased levels of advanced oxidation protein products (AOPPs) were associated with nociceptive behavior and clinical scores in an experimental progressive autoimmune encephalomyelitis model (PMS-EAE).

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.

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.

Genoprotective and hepatoprotective effects of Guarana (Paullinia cupana Mart. var. sorbilis) on CCl4-induced liver damage in rats.

CONTEXT: Several biological effects of Paullinia cupana (guarana) have been demonstrated, but little information is available on its effects on the liver. OBJECTIVE: The current study was designed to evaluate the hepatoprotective and genoprotective effects of powder seeds from guarana on CCl4-induced liver injury in rats. MATERIALS AND METHODS: Male Wistar rats were pretreated with guarana powder (100, 300 and 600 mg/kg) or silymarin 100 mg/kg daily for 14 days before treatment with a single dose of CCl4 (50% CCl4, 1 mL/kg, intraperitoneally). RESULTS: The treatment with CCl4 significantly increased the serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In addition, CCl4 increased the DNA damage index in hepatocytes. Guarana in all concentrations was effective in decreasing the ALT and AST activities when compared with the CCl4-treated group. The treatment with guarana decreased DNA damage index when compared with the CCl4-treated group. In addition, the DNA damage index showed a significant positive correlation with AST and ALT. DISCUSSION AND CONCLUSION: These results indicate that the guarana has hepatoprotective activity and prevents the DNA strand breakage in the CCl4-induced liver damage in rats.

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.

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.

Are Advanced Oxidation Protein Products (AOPPs) Levels Altered in Neuropsychiatric Disorders? An Integrative Review.

Neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are considered a public health problem since it interferes in personal relationships and at work. The pathophysiological mechanisms of these mental disorders are still not completely understood. The variety and heterogeneity of symptoms, as well as the absence of biomarkers, make the diagnosis, prognosis, and treatment of these disorders difficult. However, oxidative stress appears to play a role in the pathophysiology of these diseases. In this context, advanced oxidation protein products (AOPPs) are considered a biomarker of protein oxidative damage and have been associated with neuroinflammatory diseases. In patients with neuropsychiatric disorders, increased levels of AOPPs were associated with the severity of symptoms and decreased quality of life. Thus, the objective of this integrative review is to investigate and discuss the relationship between AOPPs levels and MDD, BD, and SZ. Different databases were consulted and approximately 112 scientific articles were found relating AOPPs and psychiatric disorders. In the majority of studies, the blood levels of AOPPs were increased in MDD, BD, and SZ and associated with the severity of the disorders. Although the association of this marker with the risk of developing one of these mental disorders is more uncertain, some studies have suggested this relationship. Of the twenty-four studies highlighted, only four did not find significant differences in AOPPs levels in patients with the disorders mentioned. In summary, it may be suggested that the assessment of AOPPs levels can be a useful tool in the evaluation of neuropsychiatric disorders, at least for prognostic evaluation. However, the role of this biomarker in the pathophysiology of mental disorders is still unclear, as well as whether reducing its levels represents a potential therapeutic strategy.

TRPA1 participation in behavioral impairment induced by chronic corticosterone administration.

RATIONALE: Major depressive disorder (MDD) is one of the most diagnosed mental disorders. Despite this, its pathophysiology remains poorly understood. In this context, basic research aims to unravel the pathophysiological mechanisms of MDD as well as investigate new targets and substances with therapeutic potential. Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane channel considered a sensor for inflammation and oxidative stress. Importantly, both inflammation and oxidative stress have been suggested as participants in the pathophysiology of MDD. However, the potential participation of TRPA1 in depressive disorder remains poorly investigated. OBJECTIVE: To investigate the involvement of the TRPA1 channel in the behavioral changes induced by chronic corticosterone administration (CCA) in male mice. METHODS: Swiss male mice were exposed to 21 days of CCA protocol and then treated with HC-030031 or A-967079, TRPA1 antagonists. Behavioral tests, analyzes of oxidative parameters and TRPA1 immunocontent were performed in the prefrontal cortex (PFC) and hippocampus (HIP). RESULTS: CCA induced despair-like behavior in mice accompanied by an increase in the levels of hydrogen peroxide (H2O2), a TRPA1 agonist, which was reversed by TRPA1 antagonists and ketamine (positive control). In addition, CCA protocol reduced the immunocontent of this channel in the HIP and showed a tendency to increase the TRPA1 protein expression in the PFC. CONCLUSION: Our work suggests that TRPA1 channel appears crucial to mediate the behavioral impairment induced by CCA in male Swiss mice.

Microglia and HPA axis in depression: An overview of participation and relationship.

Objectives: This narrative review article provides an overview on the involvement of microglia and the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of depression, as well investigates the mutual relationship between these two entities: how microglial activation can contribute to the dysregulation of the HPA axis, and vice versa.Methods: Relevant studies and reviews already published in the Pubmed electronic database involving the themes microglia, HPA axis and depression were used to meet the objectives.Results: Exposition to stressful events is considered a common factor in the mechanisms proposed to explain the depressive disorder. Stress can activate microglial cells, important immune components of the central nervous system (CNS). Moreover, another system involved in the physiological response to stressors is the hypothalamic-pituitary-adrenal (HPA) axis, the main stress response system responsible for the production of the glucocorticoid hormone (GC). Also, mediators released after microglial activation can stimulate the HPA axis, inducing production of GC. Likewise, high levels of GCs are also capable of activating microglia, generating a vicious cycle.Conclusion: Immune and neuroendocrine systems seems to work in a coordinated manner and that their dysregulation may be involved in the pathophysiology of depression since neuroinflammation and hypercortisolism are often observed in this disorder.

Lower antidepressant response to fluoxetine is associated with anxiety-like behavior, hippocampal oxidative imbalance, and increase on peripheral IL-17 and IFN-γ levels.

Major depression is a leading contributor to the global burden of disease. This is mainly related to the disorder chronic and recurrent nature, and to high rates of refractoriness to treatment. Limited efficacy with currently available antidepressants highlights the need for more effective options for treating drug-resistant patients and emphasizes the importance of developing specific preclinical models for treatment-resistant populations. Treatment-resistant depression (TRD) is commonly defined as failure to respond to two or more trials of antidepressants. In this study, we investigated the effect of fluoxetine treatment for fourteen days on the depressive-like behavior and the oxidative and inflammatory parameters of mice submitted to chronic corticosterone administration. After 21 days of subcutaneous corticosterone administration (20 mg/kg/day) and 14 days of oral fluoxetine treatment (10 mg/kg/day, started on day 7 of induction protocol), we separated animals into two groups according to the tail suspension test (TST) results: antidepressant responders (good response to antidepressant, GRA) and non-responders (resistance to antidepressant, AR). Forced swimming test (FST), elevated plus maze test (EPMT), and open field test (OFT) were performed. We found that animals classified as AR (i.e., those with higher immobility values in the TST) demonstrated anxiety-like behavior in the EPMT, increased H2O2 levels, and decreased catalase activity in the hippocampus, as well as increased serum levels of IL-17 and IFN-γ. Our findings suggest that a redox imbalance in the hippocampus, combined with increased levels of peripheral IL-17 and INF-γ, may be involved with an impaired response to fluoxetine.

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.

Advanced Oxidative Protein Products Role in Multiple Sclerosis: a Systematic Review and Meta-analysis.

Multiple sclerosis (MS) is an autoimmune-mediated disease that damages the central nervous system. MS pathophysiological features are not entirely understood, but the increase of reactive oxygen species (ROS) possibly causes myelin and oligodendrocyte degeneration. ROS-increased production generates new compounds through oxidative modifications, including advanced oxidative protein products (AOPPs). The AOPPs are oxidative stress biomarkers and inflammatory mediators commonly formed by hypochlorous acid oxidative action on albumin. Considering that AOPPs accumulation produces ROS and induces neuronal apoptosis, these may represent a new target for drug development to MS treatment and a possible biomarker to monitor the severity of the disease. Thus, this review aims to investigate if there is an alteration in the AOPPs levels in MS and its possible involvement in patient disability. The second objective is to analyze whether drugs or compounds used in MS treatment could modify the AOPPs levels. The protocol was registered in PROSPERO (CRD42020203268). The databases' search yielded 327 articles. We excluded 259 duplicated articles and evaluated 68 articles by the title and abstract. We full-text analyzed 17 articles and included 13 articles. The AOPPs levels were increased in not-treated MS patients. Furthermore, the increase in disability status was associated with AOPPs accumulation in not-treated MS patients. Additionally, the AOPPs levels were reduced in MS patients after treatment. Therefore, AOPPs seem to play a role in MS pathophysiology and may become a new target for drug development and help MS diagnosis or treatment follow-up.

Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation.

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

TRPA1 involvement in depression- and anxiety-like behaviors in a progressive multiple sclerosis model in mice.

Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1ß, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.

Polyaminergic agents modulate contextual fear extinction in rats.

Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-d-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. The bilateral intra-hippocampal administration of exogenous spermidine (2 nmol/site) immediately after, but not 6h after extinction training, facilitated the extinction of fear conditioning. The injection of the NMDAr antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction and, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development.

Apocynin as an antidepressant agent: in vivo behavior and oxidative parameters modulation.

Depression is one of the most common mood disorders, which affects one in six people at some point in life. However, the treatment of this disease is still a challenge. Chronic corticosterone administration (CCA) is a widely used animal model to study the mechanisms involved, as well as possible therapeutic strategies for the treatment of depression. Moreover, elevated oxidative stress has been observed in psychiatric disorders, including major depression and, in this context, antioxidant therapy may be a potential therapeutic alternative. In this study, we investigated the effect of seven days of treatment with apocynin, an antioxidant of natural origin, on depressive-like behavior and oxidative parameters in mice submitted to CCA. After 21 days of corticosterone administration (20 mg/Kg/day, subcutaneously, s.c.), we observed the development of depressive-like behavior with an increase in immobility time on tail suspension test and forced swimming test and reduction in total grooming time on splash test. Also, we found high superoxide dismutase activity and hydrogen peroxide levels whereas catalase activity was reduced in the prefrontal cortex, hippocampus and striatum. Seven days of treatment with apocynin (100 mg/Kg/day orally, p.o), performed immediately after corticosterone administration in the last week of protocol, was able to reverse the most of these changes, revealing its antidepressant-like effect. In conclusion, our results suggest apocynin as an antidepressant-like agent with a mechanism of action based on the attenuation of oxidative changes induced by CCA.

Nociceptive mechanisms involved in the acute and chronic phases of a complex regional pain syndrome type 1 model in mice.

Complex regional pain syndrome I (CRPS-I) is a chronic painful pathology still undertreated. CTK 01512-2 is a recombinant version of the spider peptide Phα1ß, and it functions as a voltage-gated calcium channel blocker and a transient receptor potential ankyrin 1 (TRPA1) antagonist with antinociceptive effect in different pain models. Here, we investigate the mechanisms involved in the acute and chronic nociceptive phases of a model of CPRS-I in mice and assess the antinociceptive effect of CTK 01512-2 using this model. Adult male and female mice C57BL/6 (20-30 g) were used to determine mechanical (von Frey test) or cold (acetone test) allodynia induction. Inflammatory parameters (serum and tibial nerve lactate levels, hind paw temperature and edema, or tissue cell infiltration) were evaluated after chronic post-ischemia pain (CPIP, a model of CPRS-I) induction. Anti-inflammatory and anti-neuropathic drugs or CTK 01512-2 were tested. First, we detected that CPIP-induced mechanical and cold allodynia in male and female mice in a similar way. In the acute phase (1 day after CPIP), an increase in inflammatory parameters were observed, as well as the anti-allodynic effect of anti-inflammatory compounds. In the chronic phase (17 days after CPIP), mice exhibited mechanical and cold allodynia, and anti-neuropathic drugs induced antinociception, while no inflammatory alterations were found. CTK 01512-2 reversed the CPIP allodynic effect in both nociceptive phases. Thus, this CPRS-I model can be used to understand the mechanisms involved in CPRS-I induced pain and inflammation. Besides, we observed that CTK 01512-2 has a valuable antinociceptive effect in this pain model.

TsNTxP, a non-toxic protein from Tityus serrulatus scorpion venom, induces antinociceptive effects by suppressing glutamate release in mice.

Neuropathic pain is a common type of chronic pain caused by trauma or chemotherapy. However, this type of pain is undertreated. TsNTxP is a non-toxic protein isolated from the venom of the scorpion Tityus serrulatus, and it is structurally similar to neurotoxins that interact with voltage-gated sodium channels. However, the antinociceptive properties of this protein have not been characterized. The purpose of this study was to investigate the antinociceptive effects of TsNTxP in acute and neuropathic pain models. Male and female Swiss mice (25-30 g) were exposed to different models of acute pain (tail-flick test and nociception caused by capsaicin intraplantar injection) or neuropathic pain (chronic pain syndrome induced by paclitaxel or chronic constriction injury of the sciatic nerve). Hypersensitivity to mechanical or cold stimuli were evaluated in the models of neuropathic pain. The ability of TsNTxP to alter the release of glutamate in mouse spinal cord synaptosomes was also evaluated. The results showed that TsNTxP exerted antinociceptive effects in the tail-flick test to a thermal stimulus and in the intraplantar capsaicin administration model. Furthermore, TsNTxP was non-toxic and exerted antiallodynic effects in neuropathic pain models induced by chronic constriction injury of the sciatic nerve and administration of paclitaxel. TsNTxP reduced glutamate release from mouse spinal cord synaptosomes following stimulation with potassium chloride (KCl) or capsaicin. Thus, this T. serrulatus protein may be a promising non-toxic drug for the treatment of neuropathic pain.

ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke.

Nitric oxide levels in HIV-infected, untreated patients and HIV-infected patients receiving antiretroviral therapy.

The role of nitric oxide (NO) in HIV infection is ambiguous; controversy exists around whether the levels of serum NO are increased or decreased in HIV-infected patients. Thus, it is necessary to reassess NO levels in HIV-infected patients. The aim of this study was to investigate the nitrite/nitrate metabolite (NOx) levels in HIV-infected untreated patients and in HIV-infected patients receiving highly active antiretroviral therapy (HAART), compared with HIV-uninfected individuals (control group). The HIV-infected patients enrolled in this study had been receiving HAART for at least 6 months (HIV-treated) or had not received HAART for at least 6 months (HIV-untreated group). New recommendations encourage initiating treatment in HIV-infected adults at a CD4 cell count of 500 cells/mm(3) or less. We also investigated whether levels of NOx were associated with immunophenotypic characteristic of HIV-infected patients. Our results showed a statistically significant increase in NOx levels in the HIV-untreated group (164.0 ± 166.6 µmol/L), compared with both the control (98.9 ± 59.4 µmol/L) and HIV-treated group (71.7 ± 53.3 µmol/L). Multiple regression analysis showed that the differences in NOx level were independent of gender, liver enzyme level, lipid measurement, and hematological parameters. In addition, a lower CD4/CD8 ratio was associated with higher NOx levels in HIV-infected patients. The results further revealed that NOx levels were increased in HIV infection, and that derangement of immune system function was associated with increased NO levels. The levels of NOx were found to decline with the use of HAART, which may contribute to cardiovascular disease in HIV-infected patients.

In Vitro Oxidation of Collagen Promotes the Formation of Advanced Oxidation Protein Products and the Activation of Human Neutrophils.

The accumulation of advanced oxidation protein products (AOPPs) has been linked to several pathological conditions. Here, we investigated collagen as a potential source for AOPP formation and determined the effects of hypochlorous acid (HOCl)-treated collagen (collagen-AOPPs) on human neutrophil activity. We also assessed whether alpha-tocopherol could counteract these effects. Exposure to HOCl increased the levels of collagen-AOPPs. Collagen-AOPPs also stimulated the production of AOPPs, nitric oxide (NO), superoxide radicals (O2(-)), and HOCl by neutrophils. Collagen-AOPPs induced apoptosis and decreased the number of viable cells. Alpha-tocopherol prevented the formation of collagen-AOPPs, strongly inhibited the collagen-AOPP-induced production of O2(-) and HOCl, and increased the viability of neutrophils. Our results suggest that collagen is an important protein that interacts with HOCl to form AOPPs, and consequently, collagen-AOPP formation is related to human neutrophil activation and cell death.