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Glioblastoma (GB) is the most aggressive and common type of cancer within the central nervous system (CNS). Despite the vast knowledge of its physiopathology and histology, its etiology at the molecular level has not been completely understood. Thus, attaining a cure has not been possible yet and it remains one of the deadliest types of cancer. Usually, GB is diagnosed when some symptoms have already been presented by the patient. This diagnosis is commonly based on a physical exam and imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI), together with or followed by a surgical biopsy. As these diagnostic procedures are very invasive and often result only in the confirmation of GB presence, it is necessary to develop less invasive diagnostic and prognostic tools that lead to earlier treatment to increase GB patients' quality of life. Therefore, blood-based biomarkers (BBBs) represent excellent candidates in this context. microRNAs (miRNAs) are small, non-coding RNAs that have been demonstrated to be very stable in almost all body fluids, including saliva, serum, plasma, urine, cerebrospinal fluid (CFS), semen, and breast milk. In addition, serum-circulating and exosome-contained miRNAs have been successfully used to better classify subtypes of cancer at the molecular level and make better choices regarding the best treatment for specific cases. Moreover, as miRNAs regulate multiple target genes and can also act as tumor suppressors and oncogenes, they are involved in the appearance, progression, and even chemoresistance of most tumors. Thus, in this review, we discuss how dysregulated miRNAs in GB can be used as early diagnosis and prognosis biomarkers as well as molecular markers to subclassify GB cases and provide more personalized treatments, which may have a better response against GB. In addition, we discuss the therapeutic potential of miRNAs, the current challenges to their clinical application, and future directions in the field.
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Glioblastoma , MicroRNAs , Feminino , Humanos , MicroRNAs/genética , Glioblastoma/patologia , Prognóstico , Qualidade de Vida , BiomarcadoresRESUMO
Lead (Pb2+) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb2+-induced cognitive impairment. The dams were divided into four groups: Control, Pb2+, NAC, and Pb2++NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb2++NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb2+ and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb2+ group. As expected, Pb2+ group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb2+ were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.
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Arsenic (As) is a metalloid naturally present in the environment, in food, water, soil, and air; however, its chronic exposure, even with low doses, represents a public health concern. For a long time, As was used as a pigment, pesticide, wood preservative, and for medical applications; its industrial use has recently decreased or has been discontinued due to its toxicity. Due to its versatile applications and distribution, there is a wide spectrum of human As exposure sources, mainly contaminated drinking water. The fact that As is present in drinking water implies chronic human exposure to this metalloid; it has become a worldwide health problem, since over 200 million people live where As levels exceed safe ranges. Many health problems have been associated with As chronic exposure including cancer, cardiovascular diseases, gastrointestinal disturbances, and brain dysfunctions. Because As can cross the blood-brain barrier (BBB), the brain represents a target organ where this metalloid can exert its long-term toxic effects. Many mechanisms of As neurotoxicity have been described: oxidative stress, inflammation, DNA damage, and mitochondrial dysfunction; all of them can converge, thus leading to impaired cellular functions, cell death, and in consequence, long-term detrimental effects. Here, we provide a current overview of As toxicity and integrated the global mechanisms involved in cognitive and behavioral impairment induced by As exposure show experimental strategies against its neurotoxicity.
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Intoxicação por Arsênico , Arsênio , Água Potável , Síndromes Neurotóxicas , Humanos , Arsênio/toxicidade , Intoxicação por Arsênico/complicações , Encéfalo , CogniçãoRESUMO
BACKGROUND: Clinically Isolated Syndrome (CIS) is the first clinical episode suggestive of Clinical Definite Multiple Sclerosis (CDMS). There are no reports on possible predictors of conversion to CDMS in Mexican mestizo patients. AIM OF THE STUDY: To investigate immunological markers, clinical and paraclinical findings, and the presence of herpesvirus DNA to predict the transition from CIS to CDMS in Mexican patients. METHODS: A single-center prospective cohort study was conducted with newly diagnosed patients with CIS in Mexico between 2006 and 2010. Clinical information, immunophenotype, serum cytokines, anti-myelin protein immunoglobulins, and herpes viral DNA were determined at the time of diagnosis. RESULTS: 273 patients diagnosed with CIS met the enrolment criteria; after 10 years of follow-up, 46% met the 2010 McDonald criteria for CDMS. Baseline parameters associated with conversion to CDMS were motor symptoms, multifocal syndromes, and alterations of somatosensory evoked potentials. The presence of at least one lesion on magnetic resonance imaging was the main factor associated with an increased risk of conversion to CDMS (RR 15.52, 95% CI 3.96-60.79, p = 0.000). Patients who converted to CDMS showed a significantly lower percentage of circulating regulatory T cells, cytotoxic T cells, and B cells, and the conversion to CDMS was associated with the presence of varicella-zoster virus and herpes simplex virus 1 DNA in cerebrospinal fluid and blood. CONCLUSION: There is scarce evidence in Mexico regarding the demographic and clinical aspects of CIS and CDMS. This study shows several predictors of conversion to CDMS to be considered in Mexican patients with CIS.
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Doenças Desmielinizantes , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico , Estudos Prospectivos , México/epidemiologia , Progressão da Doença , Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Glioblastoma is the most aggressive and lethal brain tumor in adults, presenting diffuse brain infiltration, necrosis, and drug resistance. Although new drugs have been approved for recurrent patients, the median survival rate is two years; therefore, new alternatives to treat these patients are required. Previous studies have reported the anticancer activity of albendazole, its active metabolite albendazole sulfoxide, and melatonin; therefore, the present study was performed to evaluate if the combination of melatonin with albendazole or with albendazole sulfoxide induces an additive or synergistic cytotoxic effect on C6 and RG2 rat glioma cells, as well as on U87 human glioblastoma cells. Drug interaction was determined by the Chou-Talalay method. We evaluated the mechanism of cell death by flow cytometry, immunofluorescence, and crystal violet staining. The cytotoxicity of the combinations was mainly synergistic. The combined treatments induced significantly more apoptotic and autophagic cell death on the glioma cell lines. Additionally, albendazole and albendazole sulfoxide inhibited proliferation independently of melatonin. Our data justify continuing with the evaluation of this proposal since the combinations could be a potential strategy to aid in the treatment of glioblastoma.
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The communication between tumor cells and the microenvironment plays a fundamental role in the development, growth and further immune escape of the tumor. This communication is partially regulated by extracellular vesicles which can direct the behavior of surrounding cells. In recent years, it has been proposed that this feature could be applied as a potential treatment against cancer, since several studies have shown that tumors treated with radiotherapy can elicit a strong enough immune response to eliminate distant metastasis; this phenomenon is called the abscopal effect. The mechanism behind this effect may include the release of extracellular vesicles loaded with damage-associated molecular patterns and tumor-derived antigens which activates an antigen-specific immune response. This review will focus on the recent discoveries in cancer cell communications via extracellular vesicles and their implication in tumor development, as well as their potential use as an immunotherapeutic treatment against cancer.
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Vesículas Extracelulares , Neoplasias , Humanos , Neoplasias/radioterapia , Comunicação Celular , Antígenos de Neoplasias , Vesículas Extracelulares/patologia , Imunoterapia , Microambiente TumoralRESUMO
Failure of therapeutic strategies for the management and recovery from traumatic spinal cord injury (SCI) is a serious concern. Dapsone (DDS) has been reported as a neuroprotective drug after SCI, although the phase after SC damage (acute or chronic) of its major impact on functional recovery has yet to be defined. Here, we evaluated DDS acute-phase anti-inflammatory effects and their impact on early functional recovery, one week after moderate SCI, and late functional recovery, 7 weeks thereafter. Female Wistar rats were randomly assigned to each of five experimental groups: sham group; four groups of rats with SCI, treated with DDS (0, 12.5, 25.0, and 37.5 mg/kg ip), starting 3 h after injury. Plasma levels of GRO/KC, and the number of neutrophils and macrophages in cell suspensions from tissue taken at the site of injury were measured as inflammation biomarkers. Hindlimb motor function of injured rats given DDS 12.5 and 25.0 mg/kg daily for 8 weeks was evaluated on the BBB open-field ordinal scale. Six hours after injury all DDS doses decreased GRO/KC plasma levels; 24 h after injury, neutrophil numbers decreased with DDS doses of 25.0 and 37.5 mg/kg; macrophage numbers decreased only at the 37.5 mg/kg dose. In the acute phase, functional recovery was dose-dependent. Final recovery scores were 57.5 and 106.2% above the DDS-vehicle treated control group, respectively. In conclusion, the acute phase dose-dependent anti-inflammatory effects of DDS impacted early motor function recovery affecting final recovery at the end of the study.
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Kynureninase (KYNU) is a kynurenine pathway (KP) enzyme that produces metabolites with immunomodulatory properties. In recent years, overactivation of KP has been associated with poor prognosis of several types of cancer, in particular by promoting the invasion, metastasis, and chemoresistance of cancer cells. However, the role of KYNU in gliomas remains to be explored. In this study, we used the available data from TCGA, CGGA and GTEx projects to analyze KYNU expression in gliomas and healthy tissue, as well as the potential contribution of KYNU in the tumor immune infiltrate. In addition, immune-related genes were screened with KYNU expression. KYNU expression correlated with the increased malignancy of astrocytic tumors. Survival analysis in primary astrocytomas showed that KYNU expression correlated with poor prognosis. Additionally, KYNU expression correlated positively with several genes related to an immunosuppressive microenvironment and with the characteristic immune tumor infiltrate. These findings indicate that KYNU could be a potential therapeutic target for modulating the tumor microenvironment and enhancing an effective antitumor immune response.
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The activation of the maternal immune system by a prenatal infection is considered a risk factor for developing psychiatric disorders in the offspring. Toxoplasma gondii is one of the pathogenic infections associated with schizophrenia. Recent studies have shown an association between high levels of IgG anti-T. gondii from mothers and their neonates, with a higher risk of developing schizophrenia. The absence of the parasite and the levels of IgGs found in the early stages of life suggest a transplacental transfer of the anti-T. gondii IgG antibodies, which could bind fetal brain structures by molecular mimicry and induce alterations in neurodevelopment. This study aimed to determine the maternal pathogenic antibodies formation that led to behavioral impairment on the progeny of rats immunized with T. gondii. Female rats were immunized prior to gestation with T. gondii lysate (3 times/once per week). The anti-T. gondii IgG levels were determined in the serum of pregestational exposed females' previous mating. After this, locomotor activity, cognitive and social tests were performed. Cortical neurotransmitter levels for dopamine and glutamate were evaluated at 60 PND in the progeny of rats immunized before gestation (Pregestational group). The maternal pathogenic antibodies were evidenced by their binding to fetal brain mimotopes in the Pregestational group and the reactivity of the serum containing anti-T. gondii IgG was tested in control fetal brains (non-immunized). These results showed that the Pregestational group presented impairment in short and long-term memory, hypoactivity and alteration in social behavior, which was also associated with a decrease in cortical glutamate and dopamine levels. We also found the IgG antibodies bound to brain mimotopes in fetuses from females immunized with T. gondii, as well as observing a strong reactivity of the serum females immunized for fetal brain structures of fetuses from unimmunized mothers. Our results suggest that the exposure to T. gondii before gestation produced maternal pathogenic antibodies that can recognize fetal brain mimotopes and lead to neurochemical and behavioral alterations in the offspring.
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Dopamina , Toxoplasma , Gravidez , Animais , Feminino , Ratos , Ácido Glutâmico , Imunoglobulina G , EncéfaloRESUMO
Indoleamine dioxygenase (IDO), a rate limiting enzyme of the tryptophan catabolism through the kynurenine pathway (KP), has been related with a lower survival and a poor patient prognosis on several solid tumors, including gliomas. However, the use of IDO inhibitors as a therapeutic strategy for tumor treatment remains controversial in clinical trials and the role of other KP enzymes on tumor progression has remained poorly understood so far. Recently, different studies on different types of cancer have pointed out the importance of KP enzymes downstream IDO. Because of this, we conducted a bioinformatic analysis of the expression of different KP enzymes and their correlation with the gene expression of molecules related to the hallmarks of cancer in transcriptomic datasets from patients with different types of brain tumors including low grade gliomas, glioblastoma multiforme, neuroblastoma, and paraganglioma and pheochromocytoma. We found that KP enzymes that drive to NAD+ synthesis are overexpressed on different brain tumors compared to brain cortex data. Moreover, these enzymes presented positive correlations with the expression of genes related to immune response modulation, angiogenesis, Signal Transducer and Activator of Transcription (STAT) signaling, and Rho GTPase expression. These correlations suggest the relevance of the expression of the KP enzymes in brain tumor pathogenesis.
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A glioblastoma is an aggressive form of a malignant glial-derived tumor with a poor prognosis despite multimodal therapy approaches. Lactate has a preponderant role in the tumor microenvironment, playing an immunoregulatory role as well as being a carbon source for tumor growth. Lactate homeostasis depends on the proper functioning of intracellular lactate regulation systems, such as transporters and enzymes involved in its synthesis and degradation, with evidence that an intracellular lactate overload generates metabolic stress on tumor cells and tumor cell death. We propose that the delivery of a lactate overload carried in nanoparticles, allowing the intracellular release of lactate, would compromise the survival of tumor cells. We synthesized and characterized silica and titania nanoparticles loaded with lactate to evaluate the cellular uptake, metabolic activity, pH modification, and cytotoxicity on C6 cells under normoxia and chemical hypoxia, and, finally, determined the survival of an orthotopic malignant glioma model after in situ administration. A dose-dependent reduction in metabolic activity of treated cells under normoxia was found, but not under hypoxia, independent of glucose concentration. Lactated-loaded silica nanoparticles were highly cytotoxic (58.1% of dead cells) and generated significant supernatant acidification. In vivo, lactate-loaded silica nanoparticles significantly increased the median survival time of malignant glioma-bearing rats (p = 0.005) when administered in situ. These findings indicate that lactate-loaded silica nanoparticles are cytotoxic on glioma cells in vitro and in vivo.
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After the discovery of prion phenomenon, the physiological role of the cellular prion protein (PrP C ) remained elusive. In the past decades, molecular and cellular analysis has shed some light regarding interactions and functions of PrP C in health and disease. PrP C , which is located mainly at the plasma membrane of neuronal cells attached by a glycosylphosphatidylinositol (GPI) anchor, can act as a receptor or transducer from external signaling. Although the precise role of PrP C remains elusive, a variety of functions have been proposed for this protein, namely, neuronal excitability and viability. Although many issues must be solved to clearly define the role of PrP C , its connection to the central nervous system (CNS) and to several misfolding-associated diseases makes PrP C an interesting pharmacological target. In a physiological context, several reports have proposed that PrP C modulates synaptic transmission, interacting with various proteins, namely, ion pumps, channels, and metabotropic receptors. PrP C has also been implicated in the pathophysiological cell signaling induced by ß-amyloid peptide that leads to synaptic dysfunction in the context of Alzheimer's disease (AD), as a mediator of Aß-induced cell toxicity. Additionally, it has been implicated in other proteinopathies as well. In this review, we aimed to analyze the role of PrP C as a transducer of physiological and pathological signaling.
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Glioblastoma (GBM) is the most common primary malignant brain tumor with a high mortality rate. The current treatment consists of surgical resection, radiation, and chemotherapy; however, the median survival rate is only 12-18 months despite these alternatives, highlighting the urgent need to find new strategies. The heterogeneity of GBM makes this tumor difficult to treat, and the immunotherapies result in an attractive approach to modulate the antitumoral immune responses favoring the tumor eradication. The immunotherapies for GMB including monoclonal antibodies, checkpoint inhibitors, vaccines, and oncolytic viruses, among others, have shown favorable results alone or as a multimodal treatment. In this review, we summarize and discuss promising immunotherapies for GBM currently under preclinical investigation as well as in clinical trials.
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Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imunoterapia , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Glioblastoma/etiologia , Glioblastoma/metabolismo , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Modelos Animais , Terapia de Alvo Molecular , Terapia Viral Oncolítica/métodos , Resultado do TratamentoRESUMO
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The enzyme indoleamine-2,3-dioxygenase (IDO), which participates in the rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP), is associated with poor prognosis in patients with GBM. The metabolites produced after tryptophan oxidation have immunomodulatory properties that can support the immunosuppressor environment. In this study, mRNA expression, protein expression, and activity of the enzyme kynurenine monooxygenase (KMO) were analyzed in GBM cell lines (A172, LN-18, U87, U373) and patient-derived astrocytoma samples. KMO mRNA expression was assessed by real-time RT-qPCR, KMO protein expression was evaluated by flow cytometry and immunofluorescence, and KMO activity was determined by quantifying 3-hydroxykynurenine by HPLC. Heterogenous patterns of both KMO expression and activity were observed among the GBM cell lines, with the A172 cell line showing the highest KMO expression and activity. Higher KMO mRNA expression was observed in glioma samples than in patients diagnosed with only a neurological disease; high KMO mRNA expression was also observed when using samples from patients with GBM in the TCGA program. The KMO protein expression was localized in GFAP+ cells in tumor tissue. These results suggest that KMO is a relevant target to be explored in glioma since it might play a role in supporting tumor metabolism and immune suppression.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Quinurenina 3-Mono-Oxigenase/genética , Adulto , Astrocitoma/enzimologia , Neoplasias Encefálicas/enzimologia , Linhagem Celular Tumoral , Feminino , Glioma/enzimologia , Glioma/genética , Humanos , Estimativa de Kaplan-Meier , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
Beer is a fermented beverage widely consumed worldwide with high nutritional and biological value due to its bioactive components. It has been described that both alcoholic and non-alcoholic beer have several nutrients derived from their ingredients including vitamins, minerals, proteins, carbohydrates, and antioxidants that make beer a potential functional supplement. Some of these compounds possess redox, anti-inflammatory and anticarcinogenic properties making the benefits of moderate beer consumption an attractive way to improve human health. Specifically, the hop cones used for beer brewing provide essential oils, bitter acids and flavonoids that are potent antioxidants and immune response modulators. This review focuses on the redox and anti-inflammatory properties of hop derivatives and summarizes the current knowledge of their neuroprotective effects.
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Anti-Inflamatórios/farmacologia , Cerveja/análise , Humulus/química , Neuroproteção/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , OxirreduçãoRESUMO
Glioblastoma is the most aggressive brain tumor with a low median survival of 14 months. The only Food and Drug Administration (FDA)-approved treatment for topical delivery of the cancer drug carmustine is Gliadel. However, its use has been associated with several side-effects, mainly provoked by a mass effect. Nitrogen-doped carbon nanotube sponges (N-CNSs) are a new type of nanomaterial exhibiting high biocompatibility, and they are able to load large amounts of hydrophobic drugs, reducing the amount of carriers. This study evaluated the use of N-CNSs as potential carmustine carriers using malignant glioma cell lines. N-CNSs were characterized by nanoparticle tracking analysis and transmission electron microscopy. The biocompatibility of N-CNSs was determined in glioma cell lines and in primary astrocytes. Afterward, N-CNSs were loaded with carmustine (1:10 w/w), and the drug and liberation efficiency, as well as cytotoxicity induction, were determined. N-CNSs presented a homogeneous size distribution formed by round nanotubes, without induced cytotoxicity, at concentrations below 40 µg/mL. The N-CNSs loaded with carmustine exhibited a continuous kinetic release of carmustine with a maximum release after 72 h. The cytotoxic effect of N-CNSs loaded with carmustine was similar to that of carmustine alone. The results demonstrated that N-CNSs are a biocompatible nanostructure that could be used as carriers for the tumoral load of large amounts of chemotherapeutic agents.
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The frequency of central nervous system infections due to herpesvirus have been studied in various populations; however, studies in Mexican mestizo patients are scant. This paper documents the frequency of herpesvirus encephalitis in Mexican mestizo patients from the National Institute of Neurology and Neurosurgery (NINN) of Mexico. To study the frequency of herpetic viral encephalitis at the NINN in the period from 2004 to 2009. We reviewed clinical records from patients with clinically suspected encephalitis; polymerase chain reaction assays were done for detection of herpesviruses in cerebrospinal fluid (CSF) samples. The total number of patients studied was 502; in 59 (12%), the diagnosis of herpetic encephalitis was confirmed by PCR-based testing of CSF. Of them, 21 (36%) were positive for herpes simplex virus type 1, 15 (25%) for Epstein-Barr virus, 10 (17%) for varicella zoster virus, 8 (14%) for cytomegalovirus, 3 (5%) for human herpesvirus 6, and 2 (3%) for herpes simplex virus 2. Our results show a varied frequency of viral encephalitis in mestizo patients due to herpesviruses in a tertiary neurological center and point out the importance of modern molecular technology to reach the etiological diagnosis in cases of encephalitis.
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Infecções por Citomegalovirus/diagnóstico , Encefalite por Varicela Zoster/diagnóstico , Encefalite Viral/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Herpes Genital/diagnóstico , Herpes Simples/diagnóstico , Infecções por Roseolovirus/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Citomegalovirus/genética , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etnologia , Infecções por Citomegalovirus/virologia , Encefalite por Varicela Zoster/epidemiologia , Encefalite por Varicela Zoster/etnologia , Encefalite por Varicela Zoster/virologia , Encefalite Viral/epidemiologia , Encefalite Viral/etnologia , Encefalite Viral/virologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/etnologia , Infecções por Vírus Epstein-Barr/virologia , Etnicidade , Feminino , Herpes Genital/epidemiologia , Herpes Genital/etnologia , Herpes Genital/virologia , Herpes Simples/epidemiologia , Herpes Simples/etnologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/patogenicidade , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/patogenicidade , Humanos , Incidência , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Estudos Retrospectivos , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/etnologia , Infecções por Roseolovirus/virologiaRESUMO
Lead (Pb) is considered a strong environmental toxin with human health repercussions. Due to its widespread use and the number of people potentially exposed to different sources of this heavy metal, Pb intoxication is recognized as a public health problem in many countries. Exposure to Pb can occur through ingestion, inhalation, dermal, and transplacental routes. The magnitude of its effects depends on several toxicity conditions: lead speciation, doses, time, and age of exposure, among others. It has been demonstrated that Pb exposure induces stronger effects during early life. The central nervous system is especially vulnerable to Pb toxicity; Pb exposure is linked to cognitive impairment, executive function alterations, abnormal social behavior, and fine motor control perturbations. This review aims to provide a general view of the cognitive consequences associated with Pb exposure during early life as well as during adulthood. Additionally, it describes the neurotoxic mechanisms associated with cognitive impairment induced by Pb, which include neurochemical, molecular, and morphological changes that jointly could have a synergic effect on the cognitive performance.
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Quinacrine (Qx), a molecule used as an antimalarial, has shown anticancer, antiprion, and antiviral activity. The most relevant antiviral activities of Qx are related to its ability to raise pH in acidic organelles, diminishing viral enzymatic activity for viral cell entry, and its ability to bind to viral DNA and RNA. Moreover, Qx has been used as an immunomodulator in cutaneous lupus erythematosus and various rheumatological diseases, by inhibiting phospholipase A2 modulating the Th1/Th2 response. The aim of this study was to evaluate the potential antiviral effect of Qx against denominated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Vero E6 cells. The cytotoxicity of Qx in Vero E6 cells was determined by the MTT assay. Afterwards, Vero E6 cells were infected with SARS-CoV-2 at different multiplicities of infections (MOIs) of 0.1 and 0.01 in the presence of Qx (0-30 µM) to determinate the half maximal effective concentration (EC50). After 48 h, the effect of Qx against SARS-CoV-2 was assessed by viral cytotoxicity and viral copy numbers, the last were determined by digital real-time RT-PCR (ddRT-PCR). Additionally, electron and confocal microscopy of Vero E6 cells infected and treated with Qx was studied. Our data show that Qx reduces SARS-CoV-2 virus replication and virus cytotoxicity, apparently by inhibition of viral ensemble, as observed by ultrastructural images, suggesting that Qx could be a potential drug for further clinical studies against coronavirus disease 2019 (COVID-19) infection.
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Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Quinacrina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Microscopia Eletrônica de Transmissão , Células Vero , Carga Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacosRESUMO
The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA's key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA's bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.