The Protective Effect of Lithium Against Rotenone may be Evolutionarily Conserved: Evidence from Eisenia fetida, a Primitive Animal with a Ganglionic Brain.

Chronic exposure to stress is a non-adaptive situation that is associated with mitochondrial dysfunction and the accumulation of reactive oxygen species (ROS), especially superoxide anion (SA). This accumulation of ROS produces damage-associated molecular patterns (DAMPs), which activate chronic inflammatory states and behavioral changes found in several mood disorders. In a previous study, we observed that an imbalance of SA triggered by rotenone (Ro) exposure caused evolutionarily conserved oxi-inflammatory disturbances and behavioral changes in Eisenia fetida earthworms. These results supported our hypothesis that SA imbalance triggered by Ro exposure could be attenuated by lithium carbonate (LC), which has anti-inflammatory properties. The initial protocol exposed earthworms to Ro (30 nM) and four different LC concentrations. LC at a concentration of 12.85 mg/L decreased SA and nitric oxide (NO) levels and was chosen to perform complementary assays: (1) neuromuscular damage evaluated by optical and scanning electron microscopy (SEM), (2) innate immune inefficiency by analysis of Eisenia spp. extracellular neutrophil traps (eNETs), and (3) behavioral changes. Gene expression was also evaluated involving mitochondrial (COII, ND1), inflammatory (EaTLR, AMP), and neuronal transmission (nAchR α5). LC attenuated the high melanized deposits in the circular musculature, fiber disarrangement, destruction of secretory glands, immune inefficiency, and impulsive behavior pattern triggered by Ro exposure. However, the effects of LC and Ro on gene expression were more heterogeneous. In summary, SA imbalance, potentially associated with mitochondrial dysfunction, appears to be an evolutionary component triggering oxidative, inflammatory, and behavioral changes observed in psychiatric disorders that are inhibited by LC exposure.

Effects of multimodal exercise program on postural balance in patients with chronic obstructive pulmonary disease: study protocol for a randomized controlled trial.

BACKGROUND: Evidence has shown that patients with chronic obstructive pulmonary disease present significant deficits in the control of postural balance when compared to healthy subjects. In view of this, it is pertinent to investigate the effects of different therapeutic strategies used alone or in association with pulmonary rehabilitation with the potential to improve postural balance and other outcomes with clinical significance in patients with chronic obstructive pulmonary disease. This study will investigate the effects of an 8-week (short-term) multimodal exercise program [inspiratory muscle training (IMT) plus neuromuscular electrical stimulation (NMES)] on postural balance in patients with chronic obstructive pulmonary disease enrolled in a pulmonary rehabilitation program compared to individualized addition of IMT or NMES to pulmonary rehabilitation or standard pulmonary rehabilitation. METHODS: This is a randomized, single-blind, 4-parallel-group trial. Forty patients with chronic obstructive pulmonary disease will be included prospectively to this study during a pulmonary rehabilitation program. Patients will be randomly assigned to one of four groups: multimodal exercise program (IMT + NMES + pulmonary rehabilitation group) or (IMT + pulmonary rehabilitation group) or (NMES + pulmonary rehabilitation group) or standard pulmonary rehabilitation group. Patients will receive two sessions per week for 8 weeks. The primary outcome will be static postural balance and secondary outcomes will include as follows: static and dynamic postural balance, fear of falling, muscle strength and endurance (peripheral and respiratory), functional capacity, health-related quality of life, muscle architecture (quadriceps femoris and diaphragm), and laboratory biomarkers. DISCUSSION: This randomized clinical trial will investigate the effects of adding of short-term multimodal exercise program, in addition to pulmonary rehabilitation program, in postural balance in patients with chronic obstructive pulmonary disease enrolled in a pulmonary rehabilitation. Furthermore, this randomized control trial will enable important directions regarding the effectiveness of short-term intervention as part of the need to expand the focus of pulmonary rehabilitation to include balance management in chronic obstructive pulmonary disease patients which will be generated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04387318. Registered on May 13, 2020.

Rotenone-exposure as cytofunctional aging model of human dermal fibroblast prior replicative senescence.

Rotenone (Ro), causes superoxide imbalance by inhibiting complex I of the mitochondrial electron transport chain, being able to serve as a model for functional skin aging by inducing cytofunctional changes in dermal fibroblasts prior to proliferative senescence. To test this hypothesis, we conducted an initial protocol to select a concentration of Ro (0.5, 1, 1.5, 2, 2.5, and 3 µM) that would induce the highest levels of the aging marker beta-galactosidase (ß-gal) in human dermal HFF-1 fibroblasts after 72 h of culture, as well as a moderate increase in apoptosis and partial G1 arrestment. We evaluated whether the selected concentration (1 µM) differentially modulated oxidative and cytofunctional markers of fibroblasts. Ro 1.0 µM increased ß-gal levels and apoptosis frequency, decreased the frequency of S/G2 cells, induced higher levels of oxidative markers, and presented a genotoxic effect. Fibroblasts exposed to Ro showed lower mitochondrial activity, extracellular collagen deposition, and fewer fibroblast cytoplasmic connections than controls. Ro triggered overexpression of the gene associated with aging (MMP-1), downregulation genes of collagen production (COL1A, FGF-2), and cellular growth/regeneration (FGF-7). The 1 µM concentration of Ro could serve as an experimental model for functional aging fibroblasts prior to replicative senescence. It could be used to identify causal aging mechanisms and strategies to delay skin aging events.

A coffee enriched with guarana, selenium, and l-carnitine (GSC) has nutrigenomic effects on oxi-inflammatory markers of relapsing-remitting multiple sclerosis patients: A pilot study.

Relapsing-remitting multiple sclerosis (RRMS) is the most common clinical course of multiple sclerosis (MS), characterized by a chronic inflammatory state and elevated levels of oxidative markers. Food supplements with potential anti-inflammatory, antioxidant and neuroprotective effects have been tested as possible adjuvants in the treatment of MS. In this sense, this pilot study was carried out with the aim of verifying whether a minimum daily dose of a guarana, selenium and l-carnitine (GSC) based multi supplement, mixed in cappuccino-type coffee, administered for 12 weeks to 28 patients with RRMS could differentially modulate oxidative blood markers (lipoperoxidation, protein carbonylation and DNA oxidation) and inflammatory blood markers (protein levels of cytokines IL-1ß, IL-6, TNF-α, IFN-γ, IL-10, gene expression of these cytokines, and NLRP3 and CASP-1 molecules, and C-reactive protein levels). The results indicate that a low concentration of GSC is capable of decreasing the plasma levels of oxidized DNA and pro-inflammatory cytokines of RRMS patients. The results support further research into the action of GSC on clinical symptoms, not only in patients with MS, but also with other neurological conditions.

Superoxide-imbalance Pharmacologically Induced by Rotenone Triggers Behavioral, Neural, and Inflammatory Alterations in the Eisenia fetida Earthworm.

BACKGROUND: Some studies have suggested that mitochondrial dysfunction and a superoxide imbalance could increase susceptibility to chronic stressful events, contributing to the establishment of chronic inflammation and the development of mood disorders. The mitochondrial superoxide imbalance induced by some molecules, such as rotenone, could be evolutionarily conserved, causing behavioral, immune, and neurological alterations in animals with a primitive central nervous system. OBJECTIVE: Behavioral, immune, and histological markers were analyzed in Eisenia fetida earthworms chronically exposed to rotenone for 14 days. METHODS: Earthworms were placed in artificial soil containing 30 nM of rotenone distributed into a plastic cup that allowed the earthworms to leave and return freely into the ground. Since these organisms prefer to be buried, the model predicted that the earthworms would necessarily have to return to the rotenone-contaminated medium, creating a stressful condition. The effect on survival behavior in the immune and histological body wall and ventral nervous ganglia (VNG) structures, as well as gene expression related to inflammation and mitochondrial and neuromuscular changes. RESULTS: Rotenone-induced loss of earthworm escape behavior and immune alterations indicated a chronic inflammatory state. Some histological changes in the body wall and VNG indicated a possible earthworm reaction aimed at protecting against rotenone. Overexpression of the nicotinic acetylcholine receptor gene (nAChR α5) in neural tissues could also help earthworms reduce the degenerative effects of rotenone on dopaminergic neurons. CONCLUSION: These data suggest that mitochondrial dysfunction could be an evolutionarily conserved element that induces inflammatory and behavioral changes related to chronic stress.

Adapted Murine Sepsis Score: Improving the Research in Experimental Sepsis Mouse Model.

The Murine Sepsis Score (MSS) is used to assess the severity of sepsis in rats and mice based on observational characteristics. The quantitative variables of glycemia, body weight, and temperature are predictors of severity in experimental models of sepsis. Therefore, our study sought to adapt the MSS with the same variables to indicate earlier the severity of the disease in murine models of the disease. Sepsis mice presented hypoglycemia, weight loss, and hypothermia. Therefore, these variables were included in the Adapted Murine Sepsis Score (A-MSS). The A-MASS presented 100% specificity and 87.5% sensibility been able to differentiate the early sepsis symptoms and its severity. The A-MSS allows an early and more complete diagnosis of sepsis in mice and might be considered as a procedure to improve the analysis of systemic sepsis dysfunction in murine experimental models.

Bone marrow mononuclear cell transplant prevents rat depression and modulates inflammatory and neurogenic molecules.

INTRODUCTION: Major depressive disorder is associated with chronic inflammation and deficient production of brain-derived neurotrophic factor (BDNF). Bone marrow mononuclear cell (BMMC) transplantation has an anti-inflammatory effect and has been proven effective in restoring non-depressive behavior. This study investigated whether BMMC transplantation can prevent the development of depression or anxiety in chronic mild stress (CMS), as well as its effect on inflammatory and neurogenic molecules. METHOD: Three groups of animals were compared: BMMC-transplanted animals subjected to CMS for 45 days, CMS non-transplanted rats, and control animals. After the CMS period, the three groups underwent the following behavioral tests: sucrose preference test (SPT), eating-related depression test (ERDT), social avoidance test (SAT), social interaction test (SIT), and elevated plus maze test (EPMT). Transplanted cell tracking and measurement of the expression of high-mobility group box 1 (HMGB1), interleukin-1ß (IL-1ß), tumor necrosis factor (TNFα), and BDNF were performed on brain and spleen tissues. RESULTS: BMMC transplantation prevented the effects of CMS in the SPT, ERDT, SAT, and SIT, while prevention was less pronounced in the EPMT. It was found to prevent increased HMGB-1 expression induced by CMS in the hippocampus and spleen, increase BDNF expression in both tissues, and prevent increased IL-1ß expression in the hippocampus alone, while no effect of the transplant was observed in the TNFα expression. In addition, no transplanted cells were found in either the brain or spleen. CONCLUSIONS: BMMC transplantation prevents the development of depression and anxiety-like behavior triggered by CMS. It could prevent increased HMGB-1 and IL-1ß expression in the hippocampus and increased BDNF expression in the same tissue. Cell treatment represents a further perspective in the research and treatment of depression and possible mood disorders.

Is there a place for cellular therapy in depression?

Although efforts have been made to improve the pharmacological treatment of depression, approximately one-third of patients with depression do not respond to conventional therapy using antidepressants. Other potential non-pharmacological therapies have been studied in the last years, including the use of mesenchymal stem cell therapies to treat depression. These therapies are reviewed here since it is clinically relevant to develop innovative therapeutics to treat psychiatric patients. Experimental data corroborate that mesenchymal stem cell therapy could be considered a potential treatment for depression based on its anti-inflammatory and neurotrophic properties. However, some clinical trials involving treatment of depression with stem cells are in progress, but with no published results. These studies and other future clinical investigations will be crucial to define how much mesenchymal stem cells can effectively be used in psychiatric clinics as a strategy for supporting depression treatment.

Amazon-derived nutraceuticals: Promises to mitigate chronic inflammatory states and neuroinflammation.

Nutraceuticals have been the focus of numerous research in recent years and accumulating data support their use for promoting some health benefits. Several nutraceuticals have been widely studied as supplements due to their functional properties ameliorating symptoms associated with neurological disorders, such as oxidative stress and chronic inflammatory states. This seems to be the case of some fruits and seeds from the Amazon Biome consumed since the pre-Columbian period that could have potential beneficial impact on the human nervous system. The beneficial activities of these food sources are possibly related to a large number of bioactive molecules including polyphenols, carotenoids, unsaturated fatty acids, vitamins, and trace elements. In this context, this review compiled the research on six Amazonian fruits and seeds species and some of the major nutraceuticals found in their composition, presenting brief mechanisms related to their protagonist action in improving inflammatory responses and neuroinflammation.

Chlorpyrifos pesticide promotes oxidative stress and increases inflammatory states in BV-2 microglial cells: A role in neuroinflammation.

The exposure to environmental stressors, such as organophosphate (OP) pesticides, has been associated with the development of neurodegenerative diseases. Chlorpyrifos (CPF) is the worldwide most used OP pesticide and one of the most hazardous pesticides as it can cross the blood-brain barrier. Since studies evaluating the effects of CPF on brain immune cells are scarce, this research investigated the oxidative and inflammatory responses of CPF exposure in murine microglial cells. BV-2 cells were exposed to different concentrations of CPF pesticide (0.3-300 µM). CPF induced activation of microglial cells, confirmed by Iba-1 and CD11b marking, and promoted microglial proliferation and cell cycle arrest at S phase. Moreover, CPF exposure increased oxidative stress production (NO, MDA, and O2∙), and upregulated pro-inflammatory cytokines (IL-1ß and NLRP3) genes expression in BV-2 cells. Overall, data showed that CPF exposure, at the lowest concentrations, acted by promoting pro-oxidative and pro-inflammatory states in microglial cells. These results provide important information on the potential role of microglial activation in CPF-induced neuroinflammation and add to the expanding knowledge on the neurotoxicity of OP.

Tucumã (Astrocaryum aculeatum) Prevents Oxidative and DNA Damage to Retinal Pigment Epithelium Cells.

Eye diseases have a negative impact on the eyesight quality of the world population. The age-related macular degeneration (AMD) draws special attention since it is a chronic disorder characterized by oxidative and inflammatory damage to the retinal epithelial pigment, which triggers progressive vision loss. In the Brazilian Amazon, Astrocaryum aculeatum is an Amazonian fruit (Tucumã) used by riverside communities in traditional medicine to treat a number of ailments. These communities have recently shown to have increased longevity and reduced prevalence of age-related morbidity. Thus, the aim of this research was to chemically characterize and analyze the in vitro antioxidant effect and molecular damage prevention of the Tucumã ethanolic extract in retinal pigment epithelium (RPE) cells in a model for AMD. The extract was chemically characterized by ultra-high-performance liquid chromatography (HPLC) coupled with diode-array detection and mass spectrophotometry (HPLC-DAD-MS). In vitro protocols were performed, and the cytopreventive effect of Tucumã on RPE cells exposed to high concentrations of superoxide anion, an oxidant and genotoxic molecule, as well as the effect of Tucumã extract on oxidative and molecular makers were assessed. Biochemical and flow cytometry analyses were conducted in these protocols. The extract presents high concentrations of caffeic acid, gallic acid, catechin, luteolin, quercetin, and rutin. Treatment did not show cytotoxic effects in cells treated only with extract at 50 µg/mL. In fact, it improved cell viability and was able to prevent necrosis and apoptosis, and oxidative and molecular damage was significantly reduced. In summary, Tucumã is an important Amazon fruit, which seems to contribute significantly to improve human health conditions, as our findings suggest that its extract has a relevant chemical matrix rich in antioxidant molecules, and its consumption could improve eye health and contribute to prevention against oxidative stress through cytoprevention, reactive oxygen species reduction, and maintenance of DNA integrity in retinal pigment epithelium (RPE) cells.

Modulatory effects of caffeic acid on purinergic and cholinergic systems and oxi-inflammatory parameters of streptozotocin-induced diabetic rats.

Diabetes mellitus (DM) is a metabolic disorder characterized by a chronic hyperglycemia state, increased oxidative stress parameters, and inflammatory processes. AIMS: To evaluate the effect of caffeic acid (CA) on ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and adenosine deaminase (ADA) enzymatic activity and expression of the A2A receptor of the purinergic system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymatic activity and expression of the α7nAChR receptor of the cholinergic system as well as inflammatory and oxidative parameters in diabetic rats. METHODS: Diabetes was induced by a single dose intraperitoneally of streptozotocin (STZ, 55 mg/kg). Animals were divided into six groups (n = 10): control/oil; control/CA 10 mg/kg; control/CA 50 mg/kg; diabetic/oil; diabetic/CA 10 mg/kg; and diabetic/CA 50 mg/kg treated for thirty days by gavage. RESULTS: CA treatment reduced ATP and ADP hydrolysis (lymphocytes) and ATP levels (serum), and reversed the increase in ADA and AChE (lymphocytes), BuChE (serum), and myeloperoxidase (MPO, plasma) activities in diabetic rats. CA treatment did not attenuate the increase in IL-1ß and IL-6 gene expression (lymphocytes) in the diabetic state; however, it increased IL-10 and A2A gene expression, regardless of the animals' condition (healthy or diabetic), and α7nAChR gene expression. Additionally, CA attenuated the increase in oxidative stress markers and reversed the decrease in antioxidant parameters of diabetic animals. CONCLUSION: Overall, our findings indicated that CA treatment positively modulated purinergic and cholinergic enzyme activities and receptor expression, and improved oxi-inflammatory parameters, thus suggesting that this phenolic acid could improve redox homeostasis dysregulation and purinergic and cholinergic signaling in the diabetic state.

Aluminum-Induced Alterations in Purinergic System Parameters of BV-2 Brain Microglial Cells.

Aluminum (Al) is ubiquitously present in the environment and known to be a neurotoxin for humans. The trivalent free Al anion (Al3+) can cross the blood-brain barrier (BBB), accumulate in the brain, and elicit harmful effects to the central nervous system (CNS) cells. Thus, evidence has suggested that Al increases the risk of developing neurodegenerative diseases, particularly Alzheimer's disease (AD). Purinergic signaling has been shown to play a role in several neurological conditions as it can modulate the functioning of several cell types, such as microglial cells, the main resident immune cells of the CNS. However, Al effects on microglial cells and the role of the purinergic system remain elusive. Based on this background, this study is aimed at assessing the modulation of Al on purinergic system parameters of microglial cells. An in vitro study was performed using brain microglial cells exposed to Al chloride (AlCl3) and lipopolysaccharide (LPS) for 96 h. The uptake of Al, metabolism of nucleotides (ATP, ADP, and AMP) and nucleoside (adenosine), and the gene expression and protein density of purinoceptors were investigated. The results showed that both Al and LPS increased the breakdown of adenosine, whereas they decreased nucleotide hydrolysis. Furthermore, the findings revealed that both Al and LPS triggered an increase in gene expression and protein density of P2X7R and A2AR receptors, whereas reduced the A1R receptor expression and density. Taken together, the results showed that Al and LPS altered the setup of the purinergic system of microglial cells. Thus, this study provides new insights into the involvement of the purinergic system in the mechanisms underlying Al toxicity in microglial cells.

Avocado oil (Persea americana) protects SH-SY5Y cells against cytotoxicity triggered by cortisol by the modulation of BDNF, oxidative stress, and apoptosis molecules.

Chronic psycho-environmental stress can induce neurological dysfunction due to an increase in cortisol levels. It is possible that some food supplements could attenuate its negative impact, such as avocado oil (AO), which is rich in fatty acids with beneficial effects on the brain. This hypothesis was tested by an in vitro model using undifferentiated neuroblastoma cells (SH-SY5Y) exposed to hydrocortisone (HC), an active cortisol molecule with and without AO-supplementation. Cortisol can induce oxidative stress, apoptosis events, and a lowering effect on brain-derived neurotrophic factor (BDNF), a neurogenic molecule. As AO protective effects on HC-exposed cells could involve these routes, some markers of these routes were compared among neuroblastoma cultures. In the first assay, the range concentrations of HC exposure that trigger cell mortality and range AO-concentrations that could revert the HC effect. AO at all concentrations tested (2-30 µg/ml) did not present a cytotoxic effect on SH-SY5Y cells, whereas HC at 0.3-10 ng/ml had a dose-dependent cytotoxic effect on these cells. From these results, HC at 10 ng/ml and AO at 5 µg/ml were chosen for mechanistic analysis. AO was able to decrease the oxidative molecules; however, both AO- and HC-induced differential and varied gene expression modulation of these enzymes. AO partially reverted the protein and gene expression of apoptotic markers that were higher in HC-exposed cells. AO also increases the BDNF levels, which are lower HC-exposed cultures. The results indicate that AO could be a beneficial supplement in situations where cortisol levels are elevated, including chronic psycho-environmental stress. PRACTICAL APPLICATIONS: Psychological chronic stress that induces high cortisol exposure has been linked to premature aging and decreased healthy life expectancy. Neurobiological models involving cortisol have suggested a neurotoxic effect of this molecule, increasing the risk of psychiatric and other CNTDs. This effect can have a high impact mainly in infants and elderly people. In child abuse situations, chronic cortisol exposure could induce extensive apoptosis events, causing impairment in synaptogenesis. In both age groups, chronic cortisol exposure increased the risk of psychiatric conditions, especially anxiety and major depression. However, it is possible that the negative effects associated with chronic cortisol exposure could be attenuated by some food supplements. This is the case for molecules acquired through diet, such as polyunsaturated fatty acids (PUFAs), including omega-3. As inadequate omega-3 levels in the brain can increase the risk factor for neuropsychiatric disorders, it is possible to infer that some from food supplements, such as avocado oil, could attenuate the neurotoxic effects of chronic cortisol exposure. This hypothesis was tested using an exploratory in vitro protocol, and the results suggested that avocado oil could be used as a cytoprotective food supplement by decreasing the oxidative stress and apoptotic events induced by cortisol.

Molecular markers associated with the outcome of tamoxifen treatment in estrogen receptor-positive breast cancer patients: scoping review and in silico analysis.

Tamoxifen (TMX) is used as adjuvant therapy for estrogen receptor-positive (ER+) breast cancer cases due to its affinity and inhibitory effects. However, about 30% of cases show drug resistance, resulting in recurrence and metastasis, the leading causes of death. A literature review can help to elucidate the main cellular processes involved in TMX resistance. A scoping review was performed to find clinical studies investigating the association of expression of molecular markers profiles with long-term outcomes in ER+ patients treated with TMX. In silico analysis was performed to assess the interrelationship among the selected markers, evaluating the joint involvement with the biological processes. Forty-five studies were selected according to the inclusion and exclusion criteria. After clustering and gene ontology analysis, 23 molecular markers were significantly associated, forming three clusters of strong correlation with cell cycle regulation, signal transduction of proliferative stimuli, and hormone response involved in morphogenesis and differentiation of mammary gland. Also, it was found that overexpression of markers in selected clusters is a significant indicator of poor overall survival. The proposed review offered a better understanding of independent data from the literature, revealing an integrative network of markers involved in cellular processes that could modulate the response of TMX. Analysis of these mechanisms and their molecular components could improve the effectiveness of TMX.

Ilex paraguariensis extract provides increased resistance against oxidative stress and protection against Amyloid beta-induced toxicity compared to caffeine in Caenorhabditis elegans.

Ilex paraguariensis is a plant from South America, used to prepare a tea-like beverage rich in caffeine and polyphenols with antioxidant proprieties. Caffeine consumption is associated with a lower risk of age-associated neuropathologies, besides several extracts that have antioxidant proprieties are known to be neuroprotective, and oxidative stress strongly correlates with Aß-toxicity. This study aims to investigate the neuroprotective effects of the Ilex paraguariensis hydroalcoholic extract (IPHE) and to evaluate if caffeine agent present in IPHE exerts neuroprotective effects in an amyloid beta-peptide (Aß)-induced toxicity in Caenorhabditis elegans. The wild-type and CL2006 worms were treated with IPHE (2 and 4 mg/mL) or caffeine (200 and 400 µM) since larval stage 1 (L1) until they achieved the required age for each assay. IPHE and caffeine increased the lifespan and appeared to act directly by reactive oxygen species (ROS) scavenger in both wild-type and CL2006 worms, also conferred resistance against oxidative stress in wild-type animals. Furthermore, both treatments delayed Aß-induced paralysis and decreased AChE activity in CL2006. The protective effect of IPHE against Aß-induced paralysis was found to be dependent on heat shock factor hsf-1 and FOXO-family transcription factor daf-16, which are respectively involved in aging-related processes and chaperone synthesis, while that of caffeine was dependent only on daf-16. Mechanistically, IPHE and caffeine decreased the levels of Aß mRNA in the CL2006 worms; however, only IPHE induced expression of the heat shock chaperonin hsp-16.2, involved in protein homeostasis. The results were overall better when treated with IPHE than with caffeine.

DNA damage and inflammatory response in workers exposed to fuels and paints.

Workers exposed to fuels and paints may present alterations in several parameters. Thus, we assessed potential biomarkers, with the aim of detecting early changes in gasoline station attendants and painters. Blood samples were collected for the analysis of inflammatory and DNA damage markers, besides biochemical, haematological and oxidative stress parameters. Biochemical and haematological parameters, which are assessed with routine exams, showed few changes. However, these findings could mask the workers' real health status. Besides, markers of oxidative damage were not modified. Levels of inflammatory parameters (cytokines and nitric oxide levels) and the DNA damage marker 8-hydroxydeoxyguanosine were significantly changed in the workers. Our results suggest that inflammatory and DNA damage parameters can be potential biomarkers for the biological monitoring of workers exposed to fuels and paints and may contribute to the development of occupational protection standards.

Aqueous extract of Paullinia cupana attenuates renal and hematological effects associated with ketoprofen.

This study aimed to evaluate the effect of aqueous extract of Paullinia cupana (AEG) against ketoprofen side effects, through biochemical, hematological, and histological parameters. AEG showed antioxidant activity in the DPPH• scavenging (IC50  = 17.00 ± 1.00 µg/ml) and HPLC analysis revealed that this extract is constituted by antioxidants (caffeine, catechins, theobromine, and polyphenols). In vivo experiments in female Wistar rats demonstrated that alterations in urea, creatinine, and uric acid levels promoted (p < .05) by ketoprofen were reversed when AEG was co-administered. Ketoprofen significantly decreased the catalase levels of animal tissues (p < .05), which were restored when AEG was co-administered with the mentioned drug. Histological analysis showed that AEG protected tissues from damages caused by ketoprofen. Moreover, AEG reestablished the number of white blood cells, which had decreased when ketoprofen was administered. In conclusion, this study suggested that the association between ketoprofen and AEG may be an alternative to reduce health damages caused by this drug. PRACTICAL APPLICATIONS: Paullinia cupana, popularly known as guaraná, is commonly consumed as a beverage in Brazil and exhibits pharmacological and beneficial effects to humans. Ketoprofen is an efficacious drug employed in the treatment of inflammatory processes. However, this drug can cause several side effects in humans. Thus, the usage of natural products and plant extracts that can reduce such undesirable effects consists in a valuable strategy to be applied in therapeutic interventions.

Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation.

Quetiapine is an antipsychotic drug that is used to treat psychiatric and neurological disorders. Despite its efficiency and low-toxicity, quetiapine administration has been associated with undesirable side effects such as the development of low-grade inflammatory disorders and neutropenia states. As the liver rapidly metabolizes quetiapine to metabolites, the non-metabolized part of this molecule might play a role in immune alterations. In an in vitro study, this hypothesis was tested by exposing activated and inactivated RAW-264.7 macrophages and human neutrophils to unmetabolized quetiapine (u-QUE). Based on our findings, u-QUE was not cytotoxic to these cells. u-QUE differentially modulates macrophages according to their activation states. In inactivated macrophages, u-QUE induced a proinflammatory state as observed by an increase in cellular proliferation; increased levels of oxidative molecules (nitric oxide and superoxide), protein levels, and gene overexpression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α); and decreased levels of IL-10, an anti-inflammatory cytokine. Conversely, on phytohemagglutinin (PHA)-activated macrophages, u-QUE exerted an anti-inflammatory effect. u-QUE induced neutrophil extracellular trap (NET) formation and increased the sensitivity of the neutrophils previously activated by exposure to dead yeast cells for NET formation. These results confirm the effect of quetiapine on macrophage and neutrophil function, which may be associated with the side effects of this psychopharmaceutical agent.