RESUMO
The intestinal immune system interacts with commensal microbiota to maintain gut homeostasis. Furthermore, stress alters the microbiome composition, leading to impaired brain function; yet how the intestinal immune system mediates these effects remains elusive. Here we report that colonic γδ T cells modulate behavioral vulnerability to chronic social stress via dectin-1 signaling. We show that reduction in specific Lactobacillus species, which are involved in T cell differentiation to protect the host immune system, contributes to stress-induced social-avoidance behavior, consistent with our observations in patients with depression. Stress-susceptible behaviors derive from increased differentiation in colonic interleukin (IL)-17-producing γδ T cells (γδ17 T cells) and their meningeal accumulation. These stress-susceptible cellular and behavioral phenotypes are causally mediated by dectin-1, an innate immune receptor expressed in γδ T cells. Our results highlight the previously unrecognized role of intestinal γδ17 T cells in the modulation of psychological stress responses and the importance of dectin-1 as a potential therapeutic target for the treatment of stress-induced behaviors.
Assuntos
Intestinos , Lectinas Tipo C , Colo , Transdução de Sinais , Receptores de Antígenos de Linfócitos T gama-deltaRESUMO
Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.
Assuntos
Modelos Animais de Doenças , Inflamação , Bulbo Olfatório , Mucosa Olfatória , Transtornos Psicóticos , Esquizofrenia , Animais , Mucosa Olfatória/patologia , Mucosa Olfatória/metabolismo , Transtornos Psicóticos/patologia , Camundongos , Humanos , Masculino , Inflamação/metabolismo , Inflamação/patologia , Bulbo Olfatório/patologia , Bulbo Olfatório/metabolismo , Feminino , Esquizofrenia/patologia , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Esquizofrenia/genética , Transtornos do Olfato/etiologia , Transtornos do Olfato/fisiopatologia , Olfato/fisiologia , Adulto , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/patologiaRESUMO
ent-Kaurene is a biosynthetic intermediate diterpene of phytohormone gibberellins, and is biosynthesized from geranylgeranyl diphosphate via ent-copalyl diphosphate (ent-CDP). The successive cyclization is catalyzed by two distinct diterpene synthases, ent-CDP synthase (ent-CPS) and ent-kaurene synthase (KS). Homologs of these diterpene synthase genes have been reported to be involved in the biosynthesis of specialized-metabolic diterpenoids for defense in several plant species, including rice (Oryza sativa). These diterpene synthases consist of three domains, αßγ domains. Active sites of ent-CPS exist at the interface of ß and γ domain, while those of KS are located within the α domain. We herein carried out domain-deletion experiments using several KSs and KS like enzymes (KSLs) to obtain insights into the roles of domains other than active-site domains. As previously reported in taxadiene synthase, deletion of γ or ßγ domains drastically decreased activities of specialized-metabolic OsKSL5, OsKSL8, OsKSL7 and OsKSL10 in O. sativa. However, unexpectedly, only α domains of several gibberellin-biosynthetic KSs, including OsKS1 in O. sativa, AtKS in Arabidopsis thaliana, TaKS in wheat (Triticum aestivum) and BdKS1 in Brachypodium distachyon, retained their original functions. Additionally, the specialized-metabolic OsKSL4, which is closely related to OsKS1, also functioned without its ßγ domains. Domain-swapping experiments showed that replacing ßγ domains in OsKSL7 with those from other KS/KSLs retained the OsKSL7 activity. Moreover, deletion of ßγ domains of bifunctional PpCPS/KS in moss (Physcomitrella patens) drastically impaired its KS-related activity. Thus, we demonstrate that monofunctional gibberellin-biosynthetic KSs are the unique diterpene synthases that retain their functions without ßγ domains.
Assuntos
Alquil e Aril Transferases , Giberelinas , Oryza , Proteínas de Plantas , Giberelinas/metabolismo , Alquil e Aril Transferases/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/química , Oryza/enzimologia , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Domínio Catalítico , Diterpenos do Tipo Caurano/metabolismo , Diterpenos do Tipo Caurano/química , Arabidopsis/genética , Arabidopsis/enzimologia , Arabidopsis/metabolismo , Diterpenos/metabolismo , Diterpenos/química , Domínios Proteicos , CatáliseRESUMO
Gibberellins are diterpenoid phytohormones that regulate plant growth, and are biosynthesized from a diterpene intermediate, ent-kaurene, which is produced from geranylgeranyl diphosphate via ent-copalyl diphosphate (ent-CDP). The successive 2 cyclization reactions are catalyzed by 2 distinct diterpene synthases, ent-CDP synthase (ent-CPS) and ent-kaurene synthase (KS). Various diterpene synthase genes involved in specialized metabolism were likely created through duplication and neofunctionalization of gibberellin-biosynthetic ent-CPS and KS genes in crops. Brachypodium distachyon is a monocotyledonous species that is a model plant in grasses. We herein found 1 ent-CPS gene homolog BdCPS and 4 tandemly arrayed KS-like genes BdKS1, KSL2, KSL3, and KSL4 in the B. distachyon genome, a simpler collection of paralogs than in crops. Phylogenetic and biochemical analyses showed that BdCPS and BdKS1 are responsible for gibberellin biosynthesis. BdKSL2 and BdKSL3 are suggested to be involved in specialized diterpenoid metabolism. Moreover, we restored KS activity of BdKSL2 through amino acid substitution.
Assuntos
Alquil e Aril Transferases , Brachypodium , Diterpenos , Giberelinas , Grão Comestível/metabolismo , Brachypodium/genética , Brachypodium/metabolismo , Filogenia , Alquil e Aril Transferases/genética , Diterpenos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Our understanding of the contribution of genetic risk factors to neuropsychiatric diseases is limited to abnormal neurodevelopment and neuronal dysfunction. Much less is known about the mechanisms whereby risk variants could affect the physiology of glial cells. Our prior studies have shown that a mutant (dominant-negative) form of a rare but highly penetrant psychiatric risk factor, Disrupted-In-Schizophrenia-1 (DISC1), impairs metabolic functions of astrocytes and leads to cognitive dysfunction. In order to overcome the limitations of the mutant DISC1 model and understand the putative regional properties of astrocyte DISC1, we assessed whether knockdown of Disc1 (Disc1-KD) in mature mouse astrocytes of the prefrontal cortex (PFC) or the hippocampus would produce behavioral abnormalities that could be attributed to astrocyte bioenergetics. We found that Disc1-KD in the hippocampus but not PFC impaired trace fear conditioning in adult mice. Using the innovative deep learning approach and convolutional deep neural networks (cDNNs), ResNet50 or ResNet18, and single cell-based analysis, we found that Disc1-KD decreased the spatial density of astrocytes associated with abnormal levels and distribution of the mitochondrial markers and the glutamate transporter, GLAST. Disc1-KD in astrocytes also led to decreased expression of the glutamatergic and increased expression of the GABA-ergic synaptic markers, possibly via non-apoptotic activation of caspase 3 in neurons located within the individual territories of Disc1-KD astrocytes. Our results indicate that altered expression of DISC1 in astrocytes could impair astrocyte bioenergetics, leading to abnormalities in synaptic neurotransmission and cognitive function in a region-dependent fashion.
Assuntos
Encéfalo/metabolismo , Cognição/fisiologia , Degeneração Neural/genética , Proteínas do Tecido Nervoso/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/patologia , Mapeamento Encefálico , Aprendizado Profundo , Técnicas de Silenciamento de Genes , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Rede Nervosa/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologiaRESUMO
Alzheimer's disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1ß or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.
Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Convulsões/metabolismo , Transmissão Sináptica , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Amiloide/genética , Animais , Inflamassomos/genética , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Levetiracetam , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piracetam/análogos & derivados , Piracetam/farmacologia , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/patologiaRESUMO
Although there are a number of clinically effective treatments for depression, many patients exhibit treatment resistance. Recent clinical and preclinical studies reveal that peripheral and brain immune changes and inflammation are involved in the pathophysiology of depression. This 'Inflamed Brain' research provides critical clues for understanding of disease pathophysiology and many candidate molecules that are potentially useful for identifying novel drug targets for the treatment of depression. In this review, we will present clinical evidence on the role of inflammation in the pathophysiology of depression. We will also summarize current clinical trials which test drugs targeting inflammation for the treatment of patients with depression. Furthermore, we will briefly provide preclinical evidence demonstrating altered immune system function and inflammation in stress-induced animal models and will discuss the future potential of inflammation-related drug targets. Collectively, inflammatory signatures identified in clinical and preclinical studies may allow us to stratify depressive patients based on biotypes, contributing to the development of novel mechanism-based interventions that target specific patient populations.
Assuntos
Encéfalo/imunologia , Encéfalo/patologia , Depressão/tratamento farmacológico , Depressão/imunologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Animais , Encéfalo/efeitos dos fármacos , Depressão/complicações , Depressão/patologia , Humanos , Inflamação/complicações , Inflamação/imunologia , Estresse Psicológico/complicações , Estresse Psicológico/imunologia , Estresse Psicológico/patologiaRESUMO
Genetic structures of two closely related butterflies, Ypthima multistriata and Y. argus, inhabiting Japan were compared based on the mitochondrial cytochrome c oxidase subunit I (COI) sequences. The former species is classified as a vulnerable species and exhibits a characteristic pattern of voltinism: univoltine and bivoltine populations are distributed in a scattered manner. The latter species is common and has a normal geographical pattern of voltinism: the number of annual generations is correlated with latitude. Our genetic analyses of these two species yielded contrasting results: a spatial analysis of molecular variance (SAMOVA) and FST between each pair of populations revealed a locally fragmented genetic structure for Y. multistriata, compared to three distinct geographic groups of Y. argus within which range-wide gene flow occurs. Although Y. argus is a common species, only the southernmost populations in Japan had higher genetic diversity, while the other populations had the same or lower levels of genetic diversity, compared to Y. multistriata. These results indicate that: 1) the degree of fragmentation of Y. multistriata populations was higher; however, markedly lower genetic diversity was not found, and 2) although Y. argus is a common species, its populations may not be genetically robust. In addition, AMOVA revealed a relationship between voltinism and genetic variation in Y. multistriata. This result suggests a phylogenetic constraint of voltinism in this butterfly.
Assuntos
Borboletas/genética , Variação Genética , Animais , Borboletas/classificação , Borboletas/enzimologia , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Fluxo Gênico , Japão , Estágios do Ciclo de Vida , Proteínas Mitocondriais/genética , Especificidade da EspécieRESUMO
BACKGROUND: Although the use of aneurysmal common iliac artery (CIA) as the landing zone during endovascular aortic aneurysm repair EVAR remains an essential procedure, this procedure may increase the risk of late complications such as ongoing CIA dilatation and type Ib endoleak (CIA-related complications). We hypothesized that incomplete sealing of the aneurysmal CIA segment during EVAR could increase the incidence of CIA-related complications. In this study, we evaluated the midterm results of EVAR with aneurysmal CIA used as the landing zone and assessed the importance of distal sealing in this procedure. METHODS: We retrospectively reviewed all cases of endovascular aneurysm repair using CIA as landing zone between 2007 and 2015 that had at least 3 years' follow-up. We defined aneurysmal CIA as maximum diameter ≥18 mm. The main outcome was the incidence of CIA-related complications. We compared midterm results between normal CIA and aneurysmal CIA. Next, we analyzed risk factors for CIA-related complications in aneurysmal CIA. RESULTS: Four complications occurred in normal CIA (mean follow-up, 66.5 ± 22.1 months); 21 occurred in aneurysmal CIA (mean follow-up, 62.2 ± 20.5 months). The 5-year portion of freedom from CIA-related complications was 97.3% in normal CIA and 69.4% in aneurysmal CIA (P < 0.001). Multivariable analysis in aneurysmal CIA showed that unsealed CIA segment length was only risk factor for CIA-related complications. Given the receiver operating characteristic curve results, we defined the unsealed CIA segment ≥10 mm as incomplete sealing. The hazard ratio for incomplete sealing associated with CIA-related complications was 3.92 (95% confidence interval 1.62-9.46, P = 0.02). CONCLUSIONS: Use of aneurysmal CIA as landing zone increases the risk of CIA-related complications. However, maximum sealing of the aneurysmal CIA segment could prevent these complications.
Assuntos
Aneurisma Aórtico/cirurgia , Implante de Prótese Vascular/efeitos adversos , Endoleak/etiologia , Procedimentos Endovasculares/efeitos adversos , Aneurisma Ilíaco/cirurgia , Artéria Ilíaca/cirurgia , Idoso , Idoso de 80 Anos ou mais , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/fisiopatologia , Prótese Vascular , Implante de Prótese Vascular/instrumentação , Bases de Dados Factuais , Endoleak/diagnóstico por imagem , Endoleak/fisiopatologia , Procedimentos Endovasculares/instrumentação , Feminino , Humanos , Aneurisma Ilíaco/diagnóstico por imagem , Aneurisma Ilíaco/fisiopatologia , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/fisiopatologia , Masculino , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Stents , Fatores de Tempo , Resultado do TratamentoRESUMO
We herein describe a patient on hemodialysis with advanced squamous cell lung cancer who was treated with chemotherapy that consisted of carboplatin(CBDCA)and paclitaxel(PTX). A 54-year-old man who was undergoing a routine hemodialysis for chronic renal failure presented with cold symptoms and was prescribed antibiotics.As no symptomatic improvement was achieved, he was referred to the Department of Internal Medicine in our hospital, where computed tomographic scan findings raised the suspicion of lung cancer.He was then referred to the Department of Surgery.A bronchoscopy detected a tumor, which obstructed the right upper lobe bronchus, and the patient was diagnosed with squamous cell carcinoma.Based on the mediastinal lymph node enlargement that extended into the contralateral hilar region, the stage was determined to be III B(c-T3N3M0), and we initiated chemotherapy.The regimen was CBDCA plus PTX.The carboplatin dose area under the curve(AUC)was 4(100 mg at a glomerular filtration rate of 0)for the first course, AUC 5 for the second course, and AUC 6 for the third to sixth courses, and the PTX dose was 200mg/m2.Only mild adverse events were noted, and the patient achieved a partial response after 6 treatment courses.Only a few reports have described chemotherapies administered to patients with lung cancer on hemodialysis, and as such, evidence of useful drugs is not yet available.This makes it difficult to select the most appropriate treatment for such patients.We report our experience with this patient, with a relevant literature review.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carboplatina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Diálise Renal , Resultado do TratamentoRESUMO
In recent years, endovascular treatment has become the first-line revascularisation method for aortoiliac artery occlusive disease. Rarely, aortoiliac artery occlusive disease may be associated with stenosis of the external iliac artery (EIA) that suggested pseudo-stenosis. We describe a case of aortoiliac artery occlusive disease with EIA stenosis without calcification or atheroma. Stent grafts were inserted from the abdominal aorta to the bilateral common iliac arteries. Pre-operative computed tomography and intravascular ultrasound findings confirmed the absence of calcification or atheroma in both EIA, suggesting that the EIA had developed pseudo-stenosis. Following endovascular treatment, the EIA diameter recovered only with balloon dilation after inflow improvement. Consideration is necessary when placing an easy stent graft in the narrow EIA during endovascular treatment for aortoiliac artery occlusive disease with EIA stenosis to avoid a potential stent graft diameter mismatch.
RESUMO
Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.
RESUMO
Axillary artery injury secondary to shoulder dislocation with humerus fracture is rare. Rupture of the axillary artery during open reduction is extremely rare. Here, we report about a rare case of a ruptured axillary artery during an open reduction for shoulder dislocation with humerus fracture. A 58-year-old man with left shoulder pain because of a fall after alcohol consumption was diagnosed as having left shoulder dislocation with a humerus fracture. He underwent open reduction surgery. During the procedure, bleeding was observed, and further examination through angiography revealed an ruptured axillary artery. To address this urgent situation, stent grafts were promptly deployed retrogradely from the brachial artery. The postoperative course was uneventful, except for brachial plexus palsy. In the emergent setting, endovascular repair is an efficient alternative to conventional open surgery for controlling bleeding when a ruptured axillary artery occur during open reduction for shoulder dislocation.
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Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. However, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is not fully understood. Here, we report that in mice, adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in a model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings suggest the microglial Cnr1 may contribute to adverse effect of cannabis exposure in genetically vulnerable individuals.
Assuntos
Dronabinol , Microglia , Animais , Camundongos , Agonistas de Receptores de Canabinoides , Variações do Número de Cópias de DNA , Dronabinol/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Receptores de Canabinoides/genéticaRESUMO
Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
RESUMO
Olfactory impairments contribute to the psychopathology of mental illnesses such as schizophrenia and depression. Recent neuroscience research has shed light on the previously underappreciated olfactory neural circuits involved in regulation of higher brain functions. Although environmental factors such as air pollutants and respiratory viral infections are known to contribute to the risk for psychiatric disorders, the role of nasal inflammation in neurobehavioral outcomes and disease pathophysiology remains poorly understood. Here, we will first provide an overview of published findings on the impact of nasal inflammation in the olfactory system. We will then summarize clinical studies on olfactory impairments in schizophrenia and depression, followed by preclinical evidence on the neurobehavioral outcomes produced by olfactory dysfunction. Lastly, we will discuss the potential impact of nasal inflammation on brain development and function, as well as how we can address the role of nasal inflammation in the pathophysiological mechanisms underlying psychiatric disorders. Considering the current outbreak of Coronavirus Disease 2019 (COVID-19), which often causes nasal inflammation and serious adverse effects for olfactory function that might result in long-lasting neuropsychiatric sequelae, this line of research is particularly critical to understanding of the potential significance of nasal inflammation in the pathophysiology of psychiatric disorders.
Assuntos
COVID-19 , Transtornos Mentais , Transtornos do Olfato , Humanos , Inflamação/complicações , Transtornos Mentais/psicologia , Transtornos do Olfato/etiologia , PsicofisiologiaRESUMO
Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress- and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulation in vitro and in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamate-induced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.
Assuntos
Estresse do Retículo Endoplasmático , Hipocampo , Morte Celular , Hipocampo/metabolismo , Oxindóis/farmacologiaRESUMO
Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences. Our lab has developed a brain-penetrant prodrug of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), JHU083, that potently inhibits brain GLS activity in mice following oral administration. To assess the therapeutic potential of JHU083, we infected mice with EcoHIV and characterized their neurobehavioral phenotypes. EcoHIV-infected mice exhibited decreased social interaction, suppressed sucrose preference, disrupted sleep during the early rest period, and increased sleep fragmentation, similar to what has been reported in PLH but not yet observed in murine models. At doses shown to inhibit microglial GLS, JHU083 treatment ameliorated all of the abnormal neurobehavioral phenotypes. To explore potential mechanisms underlying this effect, hippocampal microglia were isolated for RNA sequencing. The dysregulated genes and pathways in EcoHIV-infected hippocampal microglia pointed to disruptions in immune functions of these cells, which were partially restored by JHU083 treatment. These findings suggest that upregulation of microglial GLS may affect immune functions of these cells. Thus, brain-penetrable GLS inhibitors like JHU083 could act as a potential therapeutic modality for both glutamate excitotoxicity and aberrant immune activation in microglia in chronic HIV infection.
RESUMO
Type B aortic dissection (TBAD) is a rare but catastrophic complication of endovascular aneurysm repair (EVAR). We report two cases of TBAD occurring in the perioperative period of EVAR. The intraoperative and postoperative courses were unremarkable. Routine postoperative computed tomography angiography (CTA) revealed TBAD. Conservative treatment was successful, and no adverse aortic events occurred. TBAD that occurs in the perioperative period is likely to be iatrogenic in origin, uncomplicated, and managed with medical therapy: its prognosis is better than when the condition develops in the midterm postoperative period.
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Epidemiological evidence suggests that adverse environmental factors in the nasal cavity may increase the risk for neuropsychiatric diseases. For instance, air pollution and nasal viral infection have been underscored as risk factors for Parkinson's disease, schizophrenia, and mood disorders. These adverse factors can elicit local inflammation in the nasal cavity, which may in turn influence higher brain function. Nevertheless, evidence that directly supports their causal link is missing. To fill this knowledge gap, we used an inducible mouse model for olfactory inflammation and showed the evidence that this local pathological factor can elicit behavioral abnormalities.