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Herpes Simplex Virus type 1 (HSV-1) 1 is a neurotropic virus that has been associated with neurodegenerative disorders. The dysregulation of autophagy by HSV-1 has been proposed as a potential cause of neurodegeneration. While studies have extensively tackled the interaction between autophagy and HSV-1 in neurons, research in glial cells is currently limited. Our studies demonstrate that HSV-1 inhibits, but not completely blocks, the formation of autophagosomes in human oligodendroglioma- and astrocytoma- derived cell lines. These findings have been confirmed in murine oligodendrocyte precursor cells (OPCs). Finally, this study investigates the impact of autophagy on HSV-1 infection in glial cells. While the lack of basal autophagy in LC3B knockout glial cells does not have a significant effect on viral infection, cells without the autophagy-related protein ATG5 exhibit reduced viral production. The absence of ATG5 leads to a decrease in the transcription and replication of viral genes, as well as a delay in the initial stages of the formation of HSV-1 replication compartments. These findings indicate that while autophagy may not play a significant role in antiviral defense in glial cells, HSV-1 may be inhibiting autophagy to exploit non-canonical functions of certain components of the autophagic machinery, such as ATG5, to benefit its lifecycle.
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BACKGROUND AND PURPOSE: ApTOLL is an aptamer selected to antagonize toll-like receptor 4 (TLR4), a relevant actor for innate immunity involved in inflammatory responses in multiple sclerosis (MS) and other diseases. The currently available therapeutic arsenal to treat MS is composed of immunomodulators but, to date, there are no (re)myelinating drugs available in clinics. In our present study, we studied the effect of ApTOLL on different animal models of MS. EXPERIMENTAL APPROACH: The experimental autoimmune encephalomyelitis (EAE) model was used to evaluate the effect of ApTOLL on reducing the inflammatory component. A more direct effect on oligodendroglia was studied with the cuprizone model and purified primary cultures of murine and human oligodendrocyte precursor cells (OPCs) isolated through magnetic-activated cell sorting (MACS) from samples of brain cortex. Also, we tested these effects in an ex vivo model of organotypic cultures demyelinated with lysolecithin (LPC). KEY RESULTS: ApTOLL treatment positively impacted the clinical symptomatology of mice in the EAE and cuprizone models, which was associated with better preservation plus restoration of myelin and oligodendrocytes in the demyelinated lesions of animals. Restoration was corroborated on purified cultures of rodent and human OPCs. CONCLUSION AND IMPLICATIONS: Our findings reveal a new therapeutic approach for the treatment of inflammatory and demyelinating diseases such as MS. The molecular nature of the aptamer exerts not only an anti-inflammatory effect but also neuroprotective and remyelinating effects. The excellent safety profile demonstrated by ApTOLL in animals and humans opens the door to future clinical trials in MS patients.
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Aptâmeros de Nucleotídeos , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Esclerose Múltipla , Animais , Humanos , Esclerose Múltipla/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/imunologia , Camundongos , Aptâmeros de Nucleotídeos/farmacologia , Feminino , Cuprizona , Oligodendroglia/efeitos dos fármacos , Células Cultivadas , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismoRESUMO
Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-CreERT2 (control), Smofl/fl/NG2-CreERT2 (loss of function), and SmoM2/NG2-CreERT2 (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.
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Diferenciação Celular , Proteínas Hedgehog , Camundongos Transgênicos , Bainha de Mielina , Células Precursoras de Oligodendrócitos , Receptor Smoothened , Animais , Proteínas Hedgehog/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Receptor Smoothened/metabolismo , Receptor Smoothened/genética , Bainha de Mielina/metabolismo , Diferenciação Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Alcaloides de Veratrum/farmacologia , Camundongos , Remielinização/fisiologia , Remielinização/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/fisiologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
AIMS: Multiple sclerosis (MS) is a chronic neurological disease that currently lacks effective curative treatments. There is a need to find effective therapies, especially to reverse the progressive demyelination and neuronal damage. Oligodendrocytes form the myelin sheath around axons in the central nervous system (CNS) and oligodendrocyte precursor cells (OPCs) undergo mechanisms that enable spontaneously the partial repair of damaged lesions. The aim of this study was to discover small molecules with potential effects in demyelinating diseases, including (re)myelinating properties. METHODS: Recently, it has been shown how LRRK2 inhibition promotes oligodendrogliogenesis and therefore an efficient repair or myelin damaged lesions. Here we explored small molecules inhibiting LRRK2 as potential enhancers of primary OPCs proliferation and differentiation, and their potential impact on the clinical score of experimental autoimmune encephalomyelitys (EAE) mice, a validated model of the most frequent clinical form of MS, relapsing-remitting MS. RESULTS: One of the LRRK2 inhibitors presented in this study promoted the proliferation and differentiation of OPC primary cultures. When tested in the EAE murine model of MS, it exerted a statistically significant reduction of the clinical burden of the animals, and histological evidence revealed how the treated animals presented a reduced lesion area in the spinal cord. CONCLUSIONS: For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Células Precursoras de Oligodendrócitos , Camundongos , Animais , Encefalomielite Autoimune Experimental/patologia , Células Precursoras de Oligodendrócitos/patologia , Modelos Animais de Doenças , Bainha de Mielina/patologia , Oligodendroglia/patologia , Diferenciação Celular , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
The beginnings of cybernetics were marked by the publication of two papers in 1943. In the first one, Rosenblueth, Wiener, and Bigelow claimed that purposeful behavior is a circular process controlled by negative feedback. In the second seminal paper, McCulloch and Pitts proposed that neurons are interconnected working as logical operators. Both articles raised human-machine analogies and mathematically formulated cognitive mechanisms. These ideas ignited the interest of von Neumann, who was developing the first stored-program computer. Thus, after a preliminary meeting in 1945, a series of meetings were held between 1946 and 1953. The role of the Spanish neurophysiologist Rafael Lorente de Nó in the beginnings of cybernetics is attested not only by his participation in the core members of these Macy conferences but also for his previous description of reverberating circuits formed by a closed chain of internuncial neurons. This was the first neurobiologic demonstration of a feedback loop. Most researchers considered the central nervous system as a mere reflex organ until then; nevertheless, he demonstrated a self-sustained central activity in the nervous system, supporting the idea of self-regulating mechanisms as a key concept not just in machines but also in the brain.
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The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.
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Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/patologia , Substância Negra/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/patologia , Camundongos Endogâmicos C57BL , MamíferosRESUMO
This paper provides an assessment of COVID-19 occurrences in the Brazilian Amazon, with special emphasis on municipalities where mining activity is prevalent. It does so with a view to exploring how mining may be influencing the spread of coronavirus, not only within municipalities where the sector is widespread but also other areas of the Amazon. The analysis draws on findings from qualitative research and case studies of selected mining municipalities in Brazil. The results were analyzed by population range, and cases reported from the onset of the pandemic were mapped and evaluated. It is revealed that: (1) within the 772 municipalities in the Amazon, incidence of COVID-19 is relatively higher in the 33 largest mining localities; (2) there have been a higher proportion of COVID-19 cases in the selected municipalities than in other municipalities which have a similar population range; and (3) between 2020 and the first quarter of 2021, among the Amazon's mining municipalities, those containing gold experienced the most significant growth as well as had highest rates of infection. Overall, the results suggest that in the Brazilian Amazon, COVID-19 has spread fastest in major mining municipalities. These results and continuation of this research will provide support for decision-makers and local governments.
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OBJECTIVES: To perform a Delphi-based consensus on published evidence on image-guided interventional procedures for peripheral nerves of the lower limb (excluding Morton's neuroma) and provide clinical indications. METHODS: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around peripheral nerves in the lower limb (excluding Morton's neuroma) to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper. RESULTS: Nine statements on image-guided interventional procedures for peripheral nerves of the lower limb have been drafted. All of them received strong consensus. Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. CONCLUSION: Despite the promising results reported by published papers on image-guided interventional procedures for peripheral nerves of the lower limb, there is still a lack of evidence on the efficacy of most procedures. KEY POINTS: ⢠Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. ⢠US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. ⢠US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. The volume of local anesthetic affects the size of the blocked sensory area.
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Sistema Musculoesquelético , Radiologia , Anestésicos Locais , Consenso , Humanos , Extremidade Inferior/diagnóstico por imagem , Radiografia , Ultrassonografia de IntervençãoRESUMO
OBJECTIVES: Image-guided musculoskeletal interventional procedures around the hip are widely used in daily clinical practice. The need for clarity concerning the actual added value of imaging guidance and types of medications to be offered led the Ultrasound and the Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) to promote, with the support of its Research Committee, a collaborative project to review the published literature on image-guided musculoskeletal interventional procedures in the lower limb in order to derive a list of clinical indications. METHODS: In this article, we report the results of a Delphi-based consensus of 53 experts who reviewed the published literature for evidence on image-guided interventional procedures offered in the joint and soft tissues around the hip in order of their clinical indications. RESULTS: Ten statements concerning image-guided treatment procedures around the hip have been collected by the panel of ESSR experts. CONCLUSIONS: This work highlighted that there is still low evidence in the existing literature on some of these interventional procedures. Further large prospective randomized trials are essential to better confirm the benefits and objectively clarify the role of imaging to guide musculoskeletal interventional procedures around the hip. KEY POINTS: ⢠Expert consensus produced a list of 10 evidence-based statements on clinical indications of image-guided interventional procedures around the hip. ⢠The highest level of evidence was only reached for one statement. ⢠Strong consensus was obtained for all statements.
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Sistema Musculoesquelético , Radiologia , Consenso , Humanos , Estudos Prospectivos , Radiografia , Radiologia Intervencionista , Ultrassonografia de IntervençãoRESUMO
OBJECTIVES: Interventional procedures around the knee are widely adopted for treating different musculoskeletal conditions. A panel of experts from the Ultrasound and Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) reviewed the existing literature to assess the evidence on image-guided musculoskeletal interventional procedures around the knee, with the goal of highlighting some controversies associated with these procedures, specifically the role of imaging guidance, as well as the efficacy of the medications routinely injected. METHODS: We report the results of a Delphi-based consensus of 53 experts in musculoskeletal radiology, who reviewed the published literature for evidence on image-guided interventional procedures around the knee to derive a list of pertinent clinical indications. RESULTS: A list of 10 statements about clinical indications of image-guided procedures around the knee was created by a Delphi-based consensus. Only two of them had the highest level of evidence; all of them received 100% consensus. CONCLUSIONS: Ultrasonography guidance is strongly recommended for intra-articular and patellar tendinopathy procedures to ensure the precision and efficacy of these treatments. Prospective randomized studies remain warranted to better understand the role of imaging guidance and assess some of the medications used for interventional procedures around the knee. KEY POINTS: ⢠A list of 10 evidence-based statements on clinical indications of image-guided interventional procedures around the knee was produced by an expert panel of the ESSR. ⢠Strong consensus with 100% agreement was obtained for all statements. ⢠Two statements reached the highest level of evidence, allowing us to strongly recommend the use of ultrasonography to guide intra-articular and patellar tendon procedures to ensure higher accuracy and efficacy of these treatments.
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Radiologia , Consenso , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Estudos Prospectivos , Radiografia , Radiologia Intervencionista , Ultrassonografia de IntervençãoRESUMO
OBJECTIVES: Clarity regarding accuracy and effectiveness for interventional procedures around the foot and ankle is lacking. Consequently, a board of 53 members of the Ultrasound and Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) reviewed the published literature to evaluate the evidence on image-guided musculoskeletal interventional procedures around this anatomical region. METHODS: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around foot and ankle in order to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper that was shared with all panel members for final approval. RESULTS: A list of 16 evidence-based statements on clinical indications for image-guided musculoskeletal interventional procedures in the foot and ankle were drafted after a literature review. The highest level of evidence was reported for four statements, all receiving 100% agreement. CONCLUSION: According to this consensus, image-guided interventions should not be considered a first-level approach for treating Achilles tendinopathy, while ultrasonography guidance is strongly recommended to improve the efficacy of interventional procedures for plantar fasciitis and Morton's neuroma, particularly using platelet-rich plasma and corticosteroids, respectively. KEY POINTS: ⢠The expert panel of the ESSR listed 16 evidence-based statements on clinical indications of image-guided musculoskeletal interventional procedures in the foot and ankle. ⢠Strong consensus was obtained for all statements. ⢠The highest level of evidence was reached by four statements concerning the effectiveness of US-guided injections of corticosteroid for Morton's neuroma and PRP for plantar fasciitis.
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Tendão do Calcâneo , Sistema Musculoesquelético , Radiologia , Tendinopatia , Tornozelo/diagnóstico por imagem , Consenso , HumanosRESUMO
Multi-input multi-output (MIMO) transmission schemes have become the techniques of choice for increasing spectral efficiency in bandwidth-congested areas. However, the design of cost-effective receivers for MIMO channels remains a challenging task. The maximum likelihood detector can achieve excellent performance-usually, the best performance-but its computational complexity is a limiting factor in practical implementation. In the present work, a novel MIMO scheme using a practically feasible decoding algorithm based on the phase transmittance radial basis function (PTRBF) neural network is proposed. For some practical scenarios, the proposed scheme achieves improved receiver performance with lower computational complexity relative to the maximum likelihood decoding, thus substantially increasing the applicability of the algorithm. Simulation results are presented for MIMO-OFDM under 5G wireless Rayleigh channels so that a fair performance comparison with other reference techniques can be established.
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Algoritmos , Redes Neurais de Computação , Simulação por ComputadorRESUMO
Pio del Rio-Hortega was not only the discoverer of the microglia and oligodendroglia but also possibly the most prolific mentor of all Santiago Ramon y Cajal's disciples (Nobel awardee in Physiology or Medicine 1906 and considered as the father of modern Neuroscience). Among Río-Hortega's mentees, three exceptional women are frequently forgotten, chronologically: Pio's niece Asunción Amo del Río who worked with Río-Hortega at Madrid, Paris, and Oxford; the distinguished British neuropathologist Dorothy Russell who also worked with Don Pío at Oxford; and Amanda Pellegrino de Iraldi, the last mentee in his career. Our present work analyzes the figures of these three women who were in contact and collaborated with Don Pío del Río-Hortega, describing the influences received and the impact on their careers and the History of Neuroscience. The present work completes the contribution of women neuroscientists who worked with Cajal and his main disciples of the Spanish Neurological School both in Spain (previous work) and in other countries (present work).
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The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.
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Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Vasos Sanguíneos/metabolismo , Encéfalo/metabolismo , Neovascularização Patológica/genética , Placa Amiloide/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Vasos Sanguíneos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Placa Amiloide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
Arboviruses pose a major threat throughout the world and represent a great burden in tropical countries of South America. Although generally associated with moderate febrile illness, in more severe cases they can lead to neurological outcomes, such as encephalitis, Guillain-Barré syndrome, and Congenital Syndromes. In this context astrocytes play a central role in production of inflammatory cytokines, regulation of extracellular matrix, and control of glutamate driven neurotoxicity in the central nervous system. Here, we presented a comprehensive genome-wide transcriptome analysis of human primary astrocytes infected with Chikungunya, Mayaro, Oropouche, or Zika viruses. Analyses of differentially expressed genes (DEGs), pathway enrichment, and interactomes have shown that Alphaviruses up-regulated genes related to elastic fiber formation and N-glycosylation of glycoproteins, with down-regulation of cell cycle and DNA stability and chromosome maintenance genes. In contrast, Oropouche virus up-regulated cell cycle and DNA maintenance and condensation pathways while down-regulated extracellular matrix, collagen metabolism, glutamate and ion transporters pathways. Zika virus infection only up-regulated eukaryotic translation machinery while down-regulated interferon pathways. Reactome and integration analysis revealed a common signature in down-regulation of innate immune response, antiviral response, and inflammatory cytokines associated to interferon pathway for all arboviruses tested. Validation of interferon stimulated genes by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) corroborated our transcriptome findings. Altogether, our results showed a co-evolution in the mechanisms involved in the escape of arboviruses to antiviral immune response mediated by the interferon (IFN) pathway.
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Febre de Chikungunya , Infecção por Zika virus , Zika virus , Astrócitos , Humanos , Imunidade InataRESUMO
Phospholipases-D (PLDs) found in Loxosceles spiders' venoms are responsible for the dermonecrosis triggered by envenomation. PLDs can also induce other local and systemic effects, such as massive inflammatory response, edema, and hemolysis. Recombinant PLDs reproduce all of the deleterious effects induced by Loxosceles whole venoms. Herein, wild type and mutant PLDs of two species involved in accidents-L. gaucho and L. laeta-were recombinantly expressed and characterized. The mutations are related to amino acid residues relevant for catalysis (H12-H47), magnesium ion coordination (E32-D34) and binding to phospholipid substrates (Y228 and Y228-Y229-W230). Circular dichroism and structural data demonstrated that the mutant isoforms did not undergo significant structural changes. Immunoassays showed that mutant PLDs exhibit conserved epitopes and kept their antigenic properties despite the mutations. Both in vitro (sphingomyelinase activity and hemolysis) and in vivo (capillary permeability, dermonecrotic activity, and histopathological analysis) assays showed that the PLDs with mutations H12-H47, E32-D34, and Y228-Y229-W230 displayed only residual activities. Results indicate that these mutant toxins are suitable for use as antigens to obtain neutralizing antisera with enhanced properties since they will be based on the most deleterious toxins in the venom and without causing severe harmful effects to the animals in which these sera are produced.
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The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy.
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Esclerose Múltipla/tratamento farmacológico , Nervo Óptico/efeitos dos fármacos , Remielinização , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia de Coerência Óptica/métodos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Neuroproteção , Nervo Óptico/diagnóstico por imagem , Nervo Óptico/patologiaRESUMO
COVID-19 is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world. SARS-CoV-2 is the virus causing COVID-19. Acute respiratory distress syndrome (ARDS) is definitely one of the main clinically relevant consequences in patients with COVID-19. Starting from the earliest reports of the COVID-19 pandemic, two peculiar neurological manifestations (namely, hyposmia/anosmia and dysgeusia) were reported in a relevant proportion of patients infected by SARS-CoV-2. At present, the physiopathologic mechanisms accounting for the onset of these symptoms are not yet clarified. CXCL10 is a pro-inflammatory chemokine with a well-established role in the COVID-19-related cytokine storm and in subsequent development of ARDS. CXCL10 is also known to be involved in coronavirus-induced demyelination. On these bases, a role for CXCL10 as the common denominator between pulmonary and olfactory dysfunctions could be envisaged. The aim of the present report will be to hypothesize a role for CXCL10 in COVID-19 olfactory dysfunctions. Previous evidences supporting our hypothesis, with special emphasis to the role of CXCL10 in coronavirus-induced demyelination, the anatomical and physiological peculiarity of the olfactory system, and the available data supporting their link during COVID-19 infections, will be overviewed.
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COVID-19/complicações , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Transtornos do Olfato/imunologia , Transtornos do Olfato/virologia , Animais , Humanos , SARS-CoV-2RESUMO
The most frequent variant of multiple sclerosis (MS) is the relapsing-remitting form, characterized by symptomatic phases followed by periods of total/partial recovery. Hence, it is possible that these patients can benefit from endogenous agents that control the inflammatory process and favor spontaneous remyelination. In this context, there is increasing interest in the role of myeloid-derived suppressor cells (MDSCs) during the clinical course of experimental autoimmune encephalomyelitis (EAE). MDSCs speed up infiltrated T-cell anergy and apoptosis. In different animal models of MS, a milder disease course is related to higher presence/density of MDSCs in the periphery, and smaller demyelinated lesions in the central nervous system (CNS). These observations lead us to wonder whether MDSCs might not only exert an anti-inflammatory effect but might also have direct influence on oligodendrocyte precursor cells (OPCs) and remyelination. In the present work, we reveal for the first time the relationship between OPCs and MDSCs in EAE, relationship that is guided by the distance from the inflammatory core. We describe the effects of MDSCs on survival, proliferation, as well as potent promoters of OPC differentiation toward mature phenotypes. We show for the first time that osteopontin is remarkably present in the analyzed secretome of MDSCs. The ablation of this cue from MDSCs-secretome demonstrates that osteopontin is the main MDSC effector on these oligodendroglial cells. These data highlight a crucial pathogenic interaction between innate immunity and the CNS, opening ways to develop MDSC- and/or osteopontin-based therapies to promote effective myelin preservation and repair in MS patients.