Assuntos
Doença de Alzheimer , Astrócitos , Humanos , Astrócitos/metabolismo , Peptídeos beta-AmiloidesRESUMO
Venezuelan equine encephalitis virus (VEEV) is a mosquito borne alphavirus which leads to high viremia in equines followed by lethal encephalitis and lateral spread to humans. In addition to naturally occurring outbreaks, VEEV is a potential biothreat agent with no approved human vaccine or therapeutic currently available. Single domain antibodies (sdAb), also known as nanobodies, have the potential to be effective therapeutic agents. Using an immune phage display library derived from a llama immunized with an equine vaccine that included inactivated VEEV, five sdAb sequence families were identified that showed varying ability to neutralize VEEV. One of the sequence families had been identified previously in selections against chikungunya virus, a related alphavirus of public health concern. A key advantage of sdAb is the ability to optimize properties such as neutralization capacity through protein engineering. Neutralization of VEEV was improved by two orders of magnitude by genetically linking sdAb. One of the bivalent constructs showed effective neutralization of both VEEV and chikungunya virus. Several of the bivalent constructs neutralized VEEV in cell-based assays with reductions in the number of plaques by 50% at protein concentrations of 1 ng/mL or lower, making future evaluation of their therapeutic potential compelling.
Assuntos
Anticorpos Neutralizantes/uso terapêutico , Vírus da Encefalite Equina Venezuelana/imunologia , Encefalomielite Equina Venezuelana/prevenção & controle , Encefalomielite Equina Venezuelana/virologia , Doenças dos Cavalos/prevenção & controle , Doenças dos Cavalos/virologia , Anticorpos de Domínio Único/uso terapêutico , Animais , Anticorpos Neutralizantes/farmacologia , Cavalos , Humanos , Engenharia de Proteínas , Anticorpos de Domínio Único/farmacologiaRESUMO
Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P < .05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r = -.28, P < .05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r = -.31, P < .05) and positively associated with TNF level (r = .42, P < .01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.
Assuntos
Transtorno Autístico/metabolismo , Ritmo Circadiano , Melatonina/análogos & derivados , Glândula Pineal/metabolismo , Transtornos do Sono do Ritmo Circadiano/metabolismo , Sono , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Transtorno Autístico/complicações , Transtorno Autístico/fisiopatologia , Biomarcadores/metabolismo , Biomarcadores/urina , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Melatonina/metabolismo , Melatonina/urina , Glândula Pineal/fisiopatologia , Saliva/metabolismo , Transtornos do Sono do Ritmo Circadiano/etiologia , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Fatores de TempoAssuntos
Animais , Ratos , Cocaína , Microbioma Gastrointestinal , Melatonina , Locomoção , MitocôndriasAssuntos
Cocaína , Microbioma Gastrointestinal , Melatonina , Animais , Locomoção , Mitocôndrias , RatosRESUMO
RATIONALE, AIMS: Major affective disorders including bipolar disorder (BD) and major depressive disorder (MDD) are associated with impaired health-related quality of life (HRQoL). Oxidative stress and subtle thyroid abnormalities may play a pathophysiological role in both disorders. Thus, the current study was performed to examine whether neuro-oxidative biomarkers and thyroid-stimulating hormone (TSH) levels could predict HRQoL in BD and MDD. METHODS: This cross-sectional study enrolled 68 BD and 37 MDD patients and 66 healthy controls. The World Health Organization (WHO) QoL-BREF scale was used to assess 4 QoL subdomains. Peripheral blood malondialdehyde (MDA), advanced oxidation protein products, paraoxonaxe/CMPAase activity, a composite index of nitro-oxidative stress, and basal TSH were measured. RESULTS: In the total WHOQoL score, 17.3% of the variance was explained by increased advanced oxidation protein products and TSH levels and lowered CMPAase activity and male gender. Physical HRQoL (14.4%) was associated with increased MDA and TSH levels and lowered CMPAase activity. Social relations HRQoL (17.4%) was predicted by higher nitro-oxidative index and TSH values, while mental and environment HRQoL were independently predicted by CMPAase activity. Finally, 73.0% of the variance in total HRQoL was explained by severity of depressive symptoms, use of anticonvulsants, lower income, early lifetime emotional neglect, MDA levels, the presence of mood disorders, and suicidal ideation. CONCLUSIONS: These data show that lowered HRQoL in major affective disorders could at least in part result from the effects of lipid peroxidation, protein oxidation, lowered antioxidant enzyme activities, and higher levels of TSH.
Assuntos
Produtos da Oxidação Avançada de Proteínas/análise , Malondialdeído/análise , Transtornos do Humor , Qualidade de Vida , Tireotropina/análise , Adulto , Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Correlação de Dados , Depressão/diagnóstico , Depressão/metabolismo , Feminino , Humanos , Masculino , Transtornos do Humor/diagnóstico , Transtornos do Humor/metabolismo , Transtornos do Humor/psicologia , Sistema Nervoso/metabolismo , Estresse Oxidativo , Escalas de Graduação Psiquiátrica , Fatores de RiscoRESUMO
Early life trauma (ELT) may increase the risk towards bipolar disorder (BD) and major depression (MDD), disorders associated with activated neuro-oxidative and neuro-nitrosative stress (O&NS) pathways. It has remained elusive whether ELTs are associated with O&NS and which ELTs are associated with distinct affective disorder phenotypes. This case-control study examined patients with BD (n = 68) and MDD (n = 37) and healthy controls (n = 66). The Child Trauma Questionnaire (CTQ) was used to assess specific ELT. We measured malondialdehyde (MDA), lipid hydroperoxides (LOOH), superoxide dismutase (SOD), catalase, advanced oxidation protein products (AOPP); NO metabolites (NOx), paraoxonase 1 activity, zinc, albumin, high density lipoprotein cholesterol and -SH groups and computed z-unit weighted composite scores. Physical neglect significantly predicts higher z-unit weighted composite scores of LOOH+SOD, LOOH+SOD+NOx, LOOH+SOD+NOx + MDA and LOOH+SOD+NOx + AOPP. Sexual abuse was associated with a significantly lower composite score of zinc+albumin+SH. Emotional abuse was associated with severity of depression and anxiety, number of depressive and manic episodes, alcohol and hypnotics use, lifetime suicidal behavior and lowered quality of life. Sexual abuse was associated with an increased risk towards BD, but not MDD. ELT, especially physical neglect, may drive increased (nitro-)oxidative stress coupled with lipid and protein oxidation, which - together with emotional abuse - may play a role in severity of illness, lowered quality of life and MDD. ELTs are also associated with the onset of BD, but this link did not appear to be related to activated O&NS pathways. These novel findings deserve confirmation in prospective studies.
Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Transtorno Bipolar/metabolismo , Transtorno Depressivo/metabolismo , Peroxidação de Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Qualidade de Vida/psicologia , Tentativa de Suicídio/psicologia , Adulto , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Catalase/sangue , Estudos Transversais , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Nitrosação/fisiologia , Oxirredução , Recidiva , Ideação Suicida , Superóxido Dismutase/sangue , Inquéritos e QuestionáriosRESUMO
Patients with major affective disorders (MAFD) with comorbid anxiety show a greater functional impairment than those without anxiety. The aim of this study is to delineate the associations between severity of anxiety in MAFD, namely bipolar disorder (BD) and major depression (MDD), and MAFD characteristics and serum high-density lipoprotein (HDL)-cholesterol levels. Recruited were 82 participants with anxiety disoders and 83 without anxiety disoders, including 101 MAFD patients and 51 healthy controls. We used the Hamilton Anxiety Rating Scale (HAM-A) to measure severity of anxiety and made the diagnoses of posttraumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD) and phobias. The HAM-A score is significantly predicted by higher number of depressive episodes, GAD and phobias, childhood trauma, tobacco use disorder, metabolic syndrome and lowered HDL-cholesterol. Increased HAM-A scores are, independently from severity of depression, associated with lowered quality of life, increased disabilities and suicidal ideation. Lithium treatment significantly lowers HAM-A scores. It is concluded that severity of anxiety significantly worsens the phenomenology of MAFD. Therefore, treatments of MAFD should target increased severity of anxiety and its risk factors including low HDL-cholesterol, metabolic syndrome, childhood trauma and tobacco use disorder.
Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Transtornos de Ansiedade/psicologia , Transtorno Bipolar/psicologia , Transtorno Depressivo Maior/psicologia , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Transtornos de Ansiedade/sangue , Transtorno Bipolar/sangue , Estudos de Casos e Controles , Comorbidade , Transtorno Depressivo Maior/sangue , Feminino , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/sangue , Transtorno Obsessivo-Compulsivo/psicologia , Transtorno de Pânico/sangue , Transtorno de Pânico/psicologia , Transtornos Fóbicos/sangue , Transtornos Fóbicos/psicologia , Qualidade de Vida , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto JovemRESUMO
Evidence indicates that major depression is accompanied by increased translocation of gut commensal Gram-negative bacteria (leaky gut) and consequent activation of oxidative and nitrosative (O&NS) pathways. This present study examined the associations among chronic apical periodontitis (CAP), root canal endotoxin levels (lipopolysaccharides, LPS), O&NS pathways, depressive symptoms, and quality of life. Measurements included advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), lipid peroxides (LOOH), -sulfhydryl (SH) groups, total radical trapping antioxidant parameter (TRAP), and paraoxonase (PON)1 activity in participants with CAP, with and without depression, as well as healthy controls (no depression, no CAP). Root canal LPS levels were positively associated with CAP, clinical depression, severity of depression (as measured with the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory) and O&NS biomarkers, especially NOx and TRAP. CAP-related depression was accompanied by increased levels of NOx, LOOH, AOPP, and TRAP. In CAP participants, there was a strong correlation (r = 0.734, p < 0.001) between root canal LPS and the HDRS score. There were significant and positive associations between CAP or root canal endotoxin with the vegetative and physio-somatic symptoms of the HDRS as well as a significant inverse association between root canal endotoxin and quality of life with strong effects on psychological, environmental, and social domains. It is concluded that increased root canal LPS accompanying CAP may cause depression and a lowered quality of life, which may be partly explained by activated O&NS pathways, especially NOx thereby enhancing hypernitrosylation and thus neuroprogressive processes. Dental health and "leaky teeth" may be intimately linked to the etiology and course of depression, while significantly impacting quality of life.