Transgenerational inheritance of methylmercury and vitamin A-induced toxicological effects in a Wistar rats environmental-based model.

Mercury (Hg) and vitamin A (VitA) are two environmental factors with potential health impacts, especially during pregnancy and early childhood. Fish and seafood may present elevated levels of methylmercury (MeHg), the major Hg derivative, and VitA. This study aimed to evaluate the transgenerational effects of exposure to MeHg and/or VitA on epigenetic and toxicological parameters in a Wistar rat model. Our findings revealed persistent toxicological effects in generations F1 and F2 following low/mild doses of MeHg and/or VitA exposure during dams' (F0) gestation and breastfeeding. Toxicological effects observed in F2 included chronic DNA damage, bone marrow toxicity, altered microglial content, reduced neuronal signal, and diminished male longevity. Sex-specific patterns were also observed. Co-exposure to MeHg and VitA showed both synergistic and antagonistic effects. Additionally, the study demonstrated that MeHg and VitA affected histone methylation and caused consistent effects in F2. While MeHg exposure has been associated with transgenerational inheritance effects in other organisms, this study provides the first evidence of transgenerational inheritance of MeHg and VitA-induced toxicological effects in rodents. Although the exact mechanism is not yet fully understood, these findings suggest that MeHg and VitA may perpetuate their impacts across generations. The study highlights the need for remedial policies and interventions to mitigate the potential health problems faced by future generations exposed to MeHg or VitA. Further research is warranted to investigate the transgenerational effects beyond F2 and determine the matrilineal or patrilineal inheritance patterns.

Gut microbiota modulation by prednisolone in a rat kindling model of pentylenetetrazol (PTZ)-induced seizure.

The gut microbiota is a complex community composed by several microorganisms that interact in the maintenance of homeostasis and contribute to physiological processes, including brain function. The relationship of the taxonomic composition of the gut microbiota with neurological diseases such as autism, Parkinson's, Alzheimer's, anxiety, and depression is widely recognized. The immune system is an important intermediary between the gut microbiota and the central nervous system, being one of the communication routes of the gut-brain axis. Although the complexity of the relationship between inflammation and epilepsy has not yet been elucidated, inflammatory processes are similar in many ways to the consequences of dysbiosis and contribute to disease progression. This study aimed to analyze the taxonomic composition of the gut microbiota of rats treated with prednisolone in a kindling model of epilepsy. Male Wistar rats (90 days, n = 24) divided into four experimental groups: sodium chloride solution 0.9 g%, diazepam 2 mg/kg, prednisolone 1 mg/kg, and prednisolone 5 mg/kg administered intraperitoneally (i.p.) for 14 days. The kindling model was induced by pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. The taxonomic profile was established by applying metagenomic DNA sequencing. There was no change in alpha diversity, and the composition of the gut microbiota between prednisolone and diazepam was similar. The significant increase in Verrucomicrobia, Saccharibacteria, and Actinobacteria may be related to the protective activity against seizures and inflammatory processes that cause some cases of epilepsy. Further studies are needed to investigate the functional influence that these species have on epilepsy and the inflammatory processes that trigger it.

Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of the nigrostriatal dopaminergic neurons that are associated with motor alterations and non-motor manifestations (such as depression). Neuroinflammation is a process with a critical role in the pathogenesis of PD. In this regard, toll-like receptor 4 (TLR4) is a central mediator of immune response in PD. Moreover, there are gender-related differences in the incidence, prevalence, and clinical features of PD. Therefore, we aimed to elucidate the role of TLR4 in the sex-dependent response to dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA) in mice. Female and male adult wildtype (WT) and TLR4 knockout (TLR4-/-) mice were administered with unilateral injection of 6-OHDA in the dorsal striatum, and non-motor and motor impairments were evaluated for 30 days, followed by biochemistry analysis in the substantia nigra pars compacta (SNc), dorsal striatum, and dorsoventral cortex. Early non-motor impairments (i.e., depressive-like behavior and spatial learning deficits) induced by 6-OHDA were observed in the male WT mice but not in male TLR4-/- or female mice. Motor alterations were observed after administration of 6-OHDA in both strains, and the lack of TLR4 was also related to motor commitment. Moreover, ablation of TLR4 prevented 6-OHDA-induced dopaminergic denervation and microgliosis in the SNc, selectively in female mice. These results reinforced the existence of sex-biased alterations in PD and indicated TLR4 as a promising therapeutic target for the motor and non-motor symptoms of PD, which will help counteract the neuroinflammatory and neurodegenerative processes.

Vitrification protocol for immature Brycon orbignyanus ovarian tissue as an extinction escape strategy.

Piracanjunba (Brycon orbignyanus) is an endangered South American fish, and ovarian tissue cryopreservation is an alternative method for preserving maternal germplasm and genetic diversity. Therefore, our aim was to test a vitrification protocol for ovarian tissue containing primary growth (PG) oocytes of B. orbignyanus as a strategy to avoid the threat of extinction. Two vitrification solutions were evaluated (VS1: 1.5 M methanol + 4.5 M propylene glycol and VS2: 1.5 M methanol + 5.5 M Me2SO) and compared using control/fresh ovarian tissue. After vitrification, the following factors were analyzed: membrane integrity using trypan blue, morphology using a histological assessment, oxidative stress (total reactive antioxidant potential (TRAP) and reduced thiol [-SH]), mitochondrial activity using MTT, and DNA damage using a comet assay. The vitrified oocytes (VS1 = 24.3 ± 0.49% and VS2 = 24.8 ± 0.69%) showed higher DNA damage than the control group (control = 20.7 ± 1.03%) (P = 0.004). In contrast, in most evaluations (membrane integrity, membrane damage, oxidative stress, and mitochondrial activity), there were no discernible differences between the control group and the vitrified samples. In addition, oocyte (P = 0.883) and nuclear diameter (P = 0.118) did not change after vitrification. VS2 treatment resulted in higher nuclear damage (15.7 ± 1.45%) than in the control treatment (3.5 ± 1.19%); however, VS1 treatment did not result in significantly more damage (9.5 ± 3.01%) than in the control (P = 0.015). Therefore, the protocol for ovarian tissue vitrification tested in this study resulted in high maintenance of PG oocyte cell integrity, making it a promising alternative for B. orbignyanus maternal genome preservation.

Neurological impairment caused by Schistosoma mansoni systemic infection exhibits early features of idiopathic neurodegenerative disease.

Schistosomiasis, a neglected tropical disease caused by trematodes of the Schistosoma genus, affects over 250 million people around the world. This disease has been associated with learning and memory deficits in children, whereas reduced attention levels, impaired work capacity, and cognitive deficits have been observed in adults. Strongly correlated with poverty and lack of basic sanitary conditions, this chronic endemic infection is common in Africa, South America, and parts of Asia and contributes to inhibition of social development and low quality of life in affected areas. Nonetheless, studies on the mechanisms involved in the neurological impairment caused by schistosomiasis are scarce. Here, we used a murine model of infection with Schistosoma mansoni in which parasites do not invade the central nervous system to evaluate the consequences of systemic infection on neurologic function. We observed that systemic infection with S. mansoni led to astrocyte and microglia activation, expression of oxidative stress-induced transcription factor Nrf2, oxidative damage, Tau phosphorylation, and amyloid-ß peptide accumulation in the prefrontal cortex of infected animals. We also found impairment in spatial learning and memory as evaluated by the Morris water maze task. Administration of anthelmintic (praziquantel) and antioxidant (N-acetylcysteine plus deferoxamine) treatments was effective in inhibiting most of these phenotypes, and the combination of both treatments had a synergistic effect to prevent such changes. These data demonstrate new perspectives toward the understanding of the pathology and possible therapeutic approaches to counteract long-term effects of systemic schistosomiasis on brain function.

Incidence of lung cancer and mortality among civil construction industry workers: A protocol for a systematic review and meta-analysis.

BACKGROUND: The construction sector is one of the most stable growth industries in the world. However, many studies have suggested an association between occupational exposure in civil construction and lung cancer risk. Thus, this study aims to assess lung cancer risk in civil construction workers occupationally exposed to physical and chemical agents through a systematic review and meta-analysis. METHODS/DESIGN: Studies will be identified by searching PUBMED, Embase, SCOPUS, WEB OF SCIENCE and the reference list of included articles. Eligible study designs will be cohort, cross-sectional, and case-control studies that report occupational exposure to physical or chemical agents and lung cancer risk through mortality or incidence outcomes. A meta-analysis will be used to combine odds ratios (ORs) from case-control studies and relative risks (RR) from cohort studies. Two reviewers will independently screen articles, extract data, and assess scientific quality using standardized forms and ROBINS-E tool if available. Otherwise, the New-Castle Ottawa rating scale will be used. Any of those will also be used in combination with the GRADE approach for quality of evidence. Overall risk estimates and their corresponding 95% confidence intervals (CIs) will be obtained using the random-effects model meta-analysis. This systematic review and meta-analysis will be conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. DISCUSSION: This review will identify and synthesize studies investigating the association between occupational exposure in the construction industry and lung cancer. The findings will help governmental entities and researchers with evidence-based decision-making because they will integrate and validate the evidence on construction workers' health effects due to occupational exposure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020164209.

Obesity associated with coal ash inhalation triggers systemic inflammation and oxidative damage in the hippocampus of rats.

People with large amounts of adipose tissue are more vulnerable and more likely to develop diseases where oxidative stress and inflammation play a pivotal role, than persons with a healthy weight. Atmospheric contamination is a reality to which a large part of the worldwide population is exposed. Half of today's global electrical energy is derived from coal. Each organism, in its complexity, responds in different ways to dietary compounds and air pollution. The objective of this study was to investigate the effects of obesity and coal ash inhalation within the parameters of oxidative damage and inflammation in different regions of the brain of rats. A diet containing high-fat concentration was administered chronically to rats, along with exposure to coal ash, simulating the contamination that occurs daily throughout human life. High-resolution transmission electron microscopy was performed to identify the particles present in coal ash samples. Our results demonstrated that obese rats exposed to coal ash inhalation were more affected by oxidative damage with subsequent systemic inflammation in the hippocampus. Since there is an inflammatory predisposition caused by obesity, the inhalation of nanoparticles increases the levels of free radicals, resulting in systemic inflammation and oxidative damage, which can lead to chronic neurodegeneration.

Administration of branched-chain amino acids increases the susceptibility to lipopolysaccharide-induced inflammation in young Wistar rats.

Maple Syrup Urine Disease (MSUD) is an inborn error of the metabolism caused by defects in the branched a-ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of branched chain amino acids (BCAAs) (leucine, isoleucine and valine). Patients with MSUD present a series of neurological dysfunction. Recent studies have been associated the brain damage in the MSUD with inflammation and immune system activation. MSUD patients die within a few months of life due to recurrent metabolic crises and neurologic deterioration, often precipitated by infection or other stresses. In this regard, our previous results showed that the inflammatory process, induced by lipopolysaccharide (LPS), associated with high levels of BCAAs causes blood-brain barrier (BBB) breakdown due to hyperactivation of MMPs. Thus, we hypothesize that the synergistic action between high concentrations of BCAAs (H-BCAAs) and LPS on BBB permeability and hyperactivation of MMPs could be through an increase in the production of cytokines and RAGE protein levels. We observed that high levels of BCAA in infant rats are related to increased brain inflammation induced by LPS administration. In addition, BCAA exposure led to an increase on brain RAGE expression of young rats. The brain inflammation was characterized by enhanced levels of interleukin 1 ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and Interferon- γ (IFN-γ), and decreased content of interleukin-10 (IL-10). Therefore, MSUD is associated with a more intense neuroinflammation induced by LPS infection.

Sex-dependent effect on mitochondrial and oxidative stress parameters in the hypothalamus induced by prepubertal stress and access to high fat diet.

OBJECTIVE: Some factors related to lifestyle, including stress and high-fat diet (HFD) consumption, are associated with higher prevalence of obesity. These factors can lead to an imbalance between ROS production and antioxidant defenses and to mitochondrial dysfunctions, which, in turn, could cause metabolic impairments, favoring the development of obesity. However, little is known about the interplay between these factors, particularly at early ages, and whether long-term sex-specific changes may occur. Here, we evaluated whether social isolation during the prepubertal period only, associated or not with chronic HFD, can exert long-term effects on oxidative status parameters and on mitochondrial function in the whole hypothalamus, in a sex-specific manner. METHODS: Wistar male and female rats were divided into two groups (receiving standard chow or standard chow + HFD), that were subdivided into exposed or not to social isolation during the prepubertal period. Oxidative status parameters, and mitochondrial function were evaluated in the hypothalamus in the adult age. RESULTS: Regarding antioxidant enzymes activities, HFD decreased GPx activity in the hypothalamus, while increasing SOD activity in females. Females also presented increased total thiols; however, non-protein thiols were lower. Main effects of stress and HFD were observed in TBARS levels in males, with both factors decreasing this parameter. Additionally, HFD increased complex IV activity, and decreased mitochondrial mass in females. Complex I-III activity was higher in males compared to females. CONCLUSION: Stress during the prepubertal period and chronic consumption of HFD had persistent sex-specific effects on oxidative status, as well as on its consequences for the cell and for mitochondrial function. HFD had more detrimental effects on females, inducing oxidative imbalance, which resulted in damage to the mitochondria. This HFD-induced imbalance may be related to the development of obesity.

Guarana (Paullinia cupana Mart.) alters gut microbiota and modulates redox status, partially via caffeine in Wistar rats.

Microbiota alterations are observed in pathological conditions, and their regulation is a subject of great interest. Gut microbes are affected by diet, and plant polyphenols may have positive effect on gut microbiota; however, plant-derived extracts may have toxic effects. Guarana (Paullinia cupana Mart.) is a nontraditional medicinal plant applied worldwide. Guarana yields an alkaloid and polyphenol-rich seed with antimicrobial, antioxidant, and anti-inflammatory properties, where caffeine is the major compound. We evaluated the effects of guarana seed powder (GSP) and purified caffeine on gut microbial composition and redox and inflammatory parameters in Wistar rats after 21 days of treatment. Fecal microbiota was analyzed utilizing 16S rDNA sequencing. Antioxidant enzymes activities from liver, kidney, and colon, as well as oxidative damage markers, were evaluated. Total nonenzymatic antioxidant potential was also evaluated. Microbiota was altered by both treatments, GSP and caffeine, without loss of diversity. In the liver, the kidney, and the colon, we observed a decrease in the antioxidant enzymes activities in the GSP group with no increase in the expression of oxidative damage markers, although some enzymes were also regulated by caffeine. Taken together, these results suggested that GSP ameliorates redox parameters but negatively affected gut microbiota, partially via caffeine.

Neurobehavioral and oxidative stress alterations following methylmercury and retinyl palmitate co-administration in pregnant and lactating rats and their offspring.

Fish consumption and ubiquitous methylmercury (MeHg) exposure represent a public health problem globally. Micronutrients presented in fish affects MeHg uptake/distribution. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. The present study aimed to examine the effects of both MeHg and retinyl palmitate administered to pregnant and lactating rats. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/Kg/day) and retinyl palmitate (7500 µg RAE1/Kg/day), either individually or in combination from the gestational day 0 to weaning. In dams, maternal behavior was scored. In neonatal and infant offspring, associative learning and neurodevelopment were evaluated. Further periadolescent male and female pups were assessed for open field, habituation and object recognition using episodic-like memory paradigm. Maternal and offspring redox parameters were evaluated. Our results showed no effects of MeHg-VitA co-administration in the quality of maternal care but showed subtle alterations in the pro-oxidant response of the hippocampus. In offspring, MeHg-VitA co-exposure affected early associative learning in neonatal pups, with no further modifications in neurodevelopment, and no locomotor or exploratory alterations in later developmental stages. Habituation was altered in a sex-dependent manner, but no overall memory disturbances were encountered. Finally, MeHg-VitA co-administration reduced lipoperoxidation in male offspring hippocampus. In conclusion, VitA co-administration in dams, under our exposure protocol, can counteract the deleterious neurodevelopmental effects solely attributed to low-dose MeHg in a tissue-specific mechanism, suggesting a protective effect of VitA against MeHg-induced oxidative damage in the central nervous system, especially in the offspring. Further work is needed to confirm our findings and elucidate the molecular mechanisms of MeHg-VitA modulation. Pre-clinical assays are necessary to demonstrate the potential therapeutical use of VitA in populations directly or indirectly exposed to MeHg.

NFκB pathway analysis: An approach to analyze gene co-expression networks employing feedback cycles.

The genes of the NFκB pathway are involved in the control of a plethora of biological processes ranking from inhibition of apoptosis to metastasis in cancer. It has been described that Gliobastoma multiforme (GBM) patients carry aberrant NFκB activation, but the molecular mechanisms are not completely understood. Here, we present a NFκB pathway analysis in tumor specimens of GBM compared to non-neoplasic brain tissues, based on the different kind of cycles found among genes of a gene co-expression network constructed using quantized data obtained from the microarrays. A cycle is a closed walk with all vertices distinct (except the first and last). Thanks to this way of finding relations among genes, a more robust interpretation of gene correlations is possible, because the cycles are associated with feedback mechanisms that are very common in biological networks. In GBM samples, we could conclude that the stoichiometric relationship between genes involved in NFκB pathway regulation is unbalanced. This can be measured and explained by the identification of a cycle. This conclusion helps to understand more about the biology of this type of tumor.

Nucleotide receptors control IL-8/CXCL8 and MCP-1/CCL2 secretions as well as proliferation in human glioma cells.

Glioma cells release cytokines to stimulate inflammation that facilitates cell proliferation. Here, we show that Lipopolysaccharide (LPS) treatment could induce glioma cells to proliferate and this process was dependent on nucleotide receptor activation as well as interleukin-8 (IL-8/CXCL8) secretion. We observed that extracellular nucleotides controlled IL-8/CXCL8 and monocyte chemoattractant protein 1 (MCP-1/CCL2) release by U251MG and U87MG human glioma cell lines via P2X7 and P2Y6 receptor activation. The LPS-induced release of these cytokines was also modulated by purinergic receptor activation since IL-8 and MCP-1 release was decreased by the nucleotide scavenger apyrase as well as by the pharmacological P2Y6 receptor antagonists suramin and MRS2578. In agreement with these observations, the knockdown of P2Y6 expression decreased LPS-induced IL-8 release as well as the spontaneous release of IL-8 and MCP-1, suggesting an endogenous basal release of nucleotides. Moreover, high millimolar concentrations of ATP increased IL-8 and MCP-1 release by the glioma cells stimulated with suboptimal LPS concentration which were blocked by P2X7 and P2Y6 antagonists. Altogether, these data suggest that extracellular nucleotides control glioma growth via P2 receptor-dependent IL-8 and MCP-1 secretions.

Differential evolutionary constraints in the evolution of chemoreceptors: a murine and human case study.

Chemoreception is among the most important sensory modalities in animals. Organisms use the ability to perceive chemical compounds in all major ecological activities. Recent studies have allowed the characterization of chemoreceptor gene families. These genes present strikingly high variability in copy numbers and pseudogenization degrees among different species, but the mechanisms underlying their evolution are not fully understood. We have analyzed the functional networks of these genes, their orthologs distribution, and performed phylogenetic analyses in order to investigate their evolutionary dynamics. We have modeled the chemosensory networks and compared the evolutionary constraints of their genes in Mus musculus, Homo sapiens, and Rattus norvegicus. We have observed significant differences regarding the constraints on the orthologous groups and network topologies of chemoreceptors and signal transduction machinery. Our findings suggest that chemosensory receptor genes are less constrained than their signal transducing machinery, resulting in greater receptor diversity and conservation of information processing pathways. More importantly, we have observed significant differences among the receptors themselves, suggesting that olfactory and bitter taste receptors are more conserved than vomeronasal receptors.

Reverse engineering the neuroblastoma regulatory network uncovers MAX as one of the master regulators of tumor progression.

Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions.

MMPREDOX/NO interplay in periodontitis and its inhibition with Satureja hortensis L. essential oil.

Satureja hortensis L. is an aromatic plant with antibacterial and antibiofilm activities against periodontopathogens. Here, we attempted to find out whether the antioxidant properties of S. hortensis L. essential oil (EO) could be used to inhibit matrix metalloproteinase (MMP) activities and prevent the induction of cell death by a pro-oxidant insult. First, a landscape analysis of MMP and REDOX/nitric oxide (NO)-related genes was performed (MRN model), and array data from periodontitis patients were plotted over the newly developed model. Thereafter, the antigelatinolytic activity of S. hortensis L. EO and its preventive effect against hydrogen peroxide (H2 O2 )-induced cell death were tested in vitro (HaCaT cells). Up-regulation of MMP genes in the MRN network (except for MMP-10, -15, -16, -20, -25, and -26) and differential expression of genes coding for antioxidant enzymes were found among others in periodontitis samples. MMP2 and MMP9 were central genes in the MRN network model. Moreover, treatments with 1 and 5 µl/ml of S. hortensis L. EO inhibited both MMP-2 and MMP-9 activities, and H2 O2 -induced cell death in vitro. We concluded that S. hortensis L. EO could be a promising host-modulating agent, since oxidative stress and excessive MMP expression/activity are typical hallmarks of periodontal pathogenesis.

Changes in lymphocyte HSP70 levels in women handball players throughout 1 year of training: the role of estrogen levels

Heat shock protein 70 (HSP70) is a chaperone that maintains protein conformation during heat stress. It has recently been observed that HSP70 may be released from cells in response to increased energy demand (e.g., exercise) and/or oxidative stress. Since HSP70 levels should change in response to athletic training, we have investigated whether blood HSP70 levels in young women handball players change over a complete training season. Thirty women handball players (12-24 years old) were divided into (..) (AU)

Mitochondrial Dysfunction in Bipolar Disorder: Lessons from Brain Imaging and Molecular Markers / Disfunción mitocondrial en el trastorno bipolar: lecciones de las imágenes cerebrales y los marcadores moleculares

Bipolar disorder (BD) is a chronic major mental illness characterized by extreme mood episodes, cognitive impairment, and high rates of disability. Several lines of evidence suggest that BD may be associated with abnormalities in mitochondrial function. Here we critically review findings from brain imaging and from preclinical studies that investigated markers of energy metabolism in BD. Research with postmortem brain and peripheral tissue revealed changes in size and distribution of mitochondria, as well as decreased mitochondrial electron transport chain function, increased oxidative stress, and increased lipid and protein damage. PET imaging studies revealed decreased glucose metabolism in sub-areas of the prefrontal cortex, amygdala, and hippocampus structures in BD. On the other hand, increased lactate levels in BD have been found in cerebrospinal fluid and in gray matter by magnetic resonance spectroscopy, which suggest that distinct pathophysiological processes may be region-specific. Resting state fMRI studies have demonstrated decreased functional connectivity between fronto-limbic circuits. In conclusion, these results support the hypothesis of mitochondrial dysfunction in BD and suggest that BD is associated with decreased energy production and a shift towards anaerobic glycolysis. Such changes in energy metabolism can potentially decrease cell plasticity and ultimately disrupt brain circuits associated with mood and cognitive control.

El trastorno bipolar (TB) es una enfermedad mental crónica grave caracterizada por episodios de ánimo extremo, trastornos cognitivos y altas tasas de discapacidad. Varias líneas de evidencia sugieren que el TB puede estar asociado con anormalidades en la función mitocondrial. Aquí analizamos críticamente los hallazgos de las imágenes cerebrales y de los estudios preclínicos que han investigado los marcadores del metabolismo de energía en TB. Las investigaciones post mórtem basadas en tejidos cerebrales y tejidos periféricos revelaron cambios en el tamaño y en la distribución de las mitocondrias, además de una disminución en la funcionalidad de la cadena de transporte de electrones de las mitocondrias, un mayor estrés oxidativo y mayores daños lipídicos y proteínicos. Estudios con imágenes TEP revelan un metabolismo de glucosa disminuido en las subáreas de la corteza prefrontal, la amígdala y el hipocampo en TB. Por otro lado, se han hallado concentraciones mayores de lactato en TB en el líquido cefalorraquídeo cerebral y en la materia gris utilizando la espectroscopia con resonancia magnética, lo cual sugiere que los procesos fisiopatológicos individuales pueden ser específicos de las distintas regiones. Los estudios con resonancias magnéticas funcionales han demostrado una menor conectividad funcional entre los circuitos frontolímbicos. En conclusión, estos resultados apoyan la hipótesis de una disfunción mitocondrial en el TB y sugieren que el TB está asociado con una menor producción de energía y un cambio hacia la glicólisis anaeróbica. Estos cambios en el metabolismo energético pueden disminuir potencialmente la plasticidad celular y, en últimas, perturbar los circuitos cerebrales asociados con el estado de ánimo y el control cognitivo.

Antioxidant treatment reverses organ failure in rat model of sepsis: role of antioxidant enzymes imbalance, neutrophil infiltration, and oxidative stress.

BACKGROUND: Some of the postulated molecular mechanisms of sepsis progression are linked with the imbalance between reactive oxygen species (ROS) production and its degradation by cellular antioxidant pathways. Some studies have correlated plasma oxidative stress, inflammatory markers, and clinical markers of organ failure, but none performed this in a systematic way, determining in situ oxidative and inflammatory markers and correlating these with markers of organ failure. MATERIALS AND METHODS: Rats subjected to cecal ligation and puncture (CLP) were treated with basic support or antioxidants and killed 12 h after to determine thiobarbituric acid reactive species (as an index of oxidative damage), superoxide dismutase (SOD), catalase (CAT), and myeloperoxidase (MPO) (as an index of neutrophil infiltration) in the kidney and lung. In addition, protein content in bronchoalveolar lavage fluid (as an index of lung alveolo-capillary dysfunction) and plasma urea (as an index of kidney injury) were measured at the same time. RESULTS: In the CLP group, we found a positive correlation between thiobarbituric acid reactive species (TBARS) and markers of organ injury in lung and kidney. Oxidative damage is correlated with an increase in SOD/CAT ratio only in the lung. In contrast, oxidative damage is correlated with MPO activity in the kidney, but not lung, suggesting different sources of oxidative damage depending on the analyzed organ. These reflect differences on the effects of basic support and antioxidants on organ dysfunction after sepsis. CONCLUSION: Despite the general occurrence of oxidative damage in different organs during sepsis development and a positive correlation between oxidative markers and organ injury, antioxidant effects seemed to depend not only on the diminution of oxidative damage but also on its anti-inflammatory activity.

Vitamin A supplementation for different periods alters rat vascular redox parameters

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Vitamin A plays physiological and antioxidants properties and is associated with protective effects on arterial level. However, deleterious effects have been reported, including those observed by our group, which has demonstrated pro-oxidant properties in other systems. Therefore, it is needed to better understand the redox effects of retinoids on arterial system. Thus, our aim was to compare vascular redox parameters among animals supplemented or not with vitamin A. Eighty-five adult male rats were treated with different retinyl palmitate (..) (AU)