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Homozygous VPS50 variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. VPS50 encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic VPS50 variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire VPS50 gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both VPS50 variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with VPS50 pathogenic variants. The VPS50-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.
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Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the POGZ regulatory targets, aiming to uncover the molecular pathways that, when disrupted by POGZ loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between POGZ targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.
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Transtornos do Neurodesenvolvimento , Fenótipo , Transtornos do Sono-Vigília , Humanos , Transtornos do Neurodesenvolvimento/genética , Transtornos do Sono-Vigília/genética , Masculino , Feminino , Sono/genética , Criança , Pré-Escolar , Ritmo Circadiano/genética , Proteínas de Ligação a DNA , Proteínas de Ciclo CelularRESUMO
BACKGROUND: Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. METHODS: Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. RESULTS: We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. CONCLUSIONS: Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.
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Distonia , Distúrbios Distônicos , Animais , Humanos , Distonia/genética , Distonia/diagnóstico , Distúrbios Distônicos/genética , Distúrbios Distônicos/diagnóstico , Testes Genéticos , Turquia , Biologia Molecular , Mutação , Proteínas de Ligação a DNA/genética , Proteínas Reguladoras de Apoptose/genéticaRESUMO
Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2 Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.
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Núcleo Celular , Proteínas de Neoplasias , Humanos , Núcleo Celular/metabolismo , Núcleo Celular/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Mutação , Fenótipo , Artrogripose/genética , Artrogripose/patologia , Citoplasma/metabolismo , Citoplasma/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Transporte Proteico , Células HEK293 , Hipopituitarismo , Fácies , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Intrinsicamente Desordenadas , Transtornos da Impressão Genômica , Deficiências do Desenvolvimento , Transtornos CromossômicosRESUMO
Ginsenosides are the primary component discernible from ginseng, including Rb1, Rb2, Rd, Rg1, Rg2, and compound K, and so forth. They have been shown to have multiple pharmacological activities. In recent years, more and more studies have been devoted to the neuroprotection of various ginsenosides against neurological diseases and their potential mechanisms. This paper comprehensively summarizes and reviews the neuroprotective effects of various ginsenosides on neurological diseases, especially acute and chronic neurodegenerative diseases, and their mechanisms, as well as their potential therapeutic applications to promote neuroprotection in disease prevention, treatment, and prognosis. Briefly, ginsenosides exert effective neuroprotective effects on neurological conditions, including stroke, Alzheimer's disease, Parkinson's disease, and brain/spinal cord injuries through a variety of molecular mechanisms, including anti-inflammatory, antioxidant, and anti-apoptotic. Among them, some signaling pathways play important roles in related processes, such as PI3K/Akt, TLR4/NF-κB, ROS/TXNIP/NLRP3, HO-1/Nrf2, Wnt/ß-catenin, and Ca2+ pathway. In conclusion, the present study reviews the research progress on the neuroprotective effects of ginsenosides in the last decade, with the aim of furnishing essential theoretical underpinning and effective references for further research and exploration of the multiple medicinal values of Chinese herbal medicines and their small molecule compounds, including ginseng and panax ginseng. Because there is less evidence in the existing clinical studies, future research should be focused on clinical trials in order to truly reflect the clinical value of various ginsenosides for the benefit of patients.
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Central nervous system (CNS) disorders represent the leading cause of disability and the second leading cause of death worldwide, and impose a substantial economic burden on society. In recent years, emerging evidence has found that beta2 -microglobulin (B2M), a subunit of major histocompatibility complex class I (MHC-I) molecules, plays a crucial role in the development and progression in certain CNS diseases. On the one hand, intracellular B2M was abnormally upregulated in brain tumors and regulated tumor microenvironments and progression. On the other hand, soluble B2M was also elevated and involved in pathological stages in CNS diseases. Targeted B2M therapy has shown promising outcomes in specific CNS diseases. In this review, we provide a comprehensive summary and discussion of recent advances in understanding the pathological processes involving B2M in CNS diseases (e.g., Alzheimer's disease, aging, stroke, HIV-related dementia, glioma, and primary central nervous system lymphoma).
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Doenças do Sistema Nervoso Central , Microglobulina beta-2 , Humanos , Microglobulina beta-2/metabolismo , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , AnimaisRESUMO
OBJECTIVES: Cytotoxic lesions of the corpus callosum (CLOCC) are a common magnetic resonance imaging (MRI) finding associated with various systemic diseases including COVID-19. Although an increasing number of such cases is reported in the literature, there is a lack of systematic evidence summarizing the etiology and neuroimaging findings of these lesions. Thus, the aim of this systematic review was to synthesize the applied nomenclature, neuroimaging and clinical features, and differential diagnoses as well as associated disease entities of CLOCC. MATERIALS AND METHODS: A comprehensive literature search in three biomedical databases identified 441 references, out of which 324 were eligible for a narrative summary including a total of 1353 patients. RESULTS: Our PRISMA-conform systematic review identifies a broad panel of disease entities which are associated with CLOCC, among them toxic/drug-treatment-associated, infectious (viral, bacterial), vascular, metabolic, traumatic, and neoplastic entities in both adult and pediatric individuals. On MRI, CLOCC show typical high T2 signal, low T1 signal, restricted diffusion, and lack of contrast enhancement. The majority of the lesions were reversible within the follow-up period (median follow-up 3 weeks). Interestingly, even though CLOCC were mostly associated with symptoms of the underlying disease, in exceptional cases, CLOCC were associated with callosal neurological symptoms. Of note, employed nomenclature for CLOCC was highly inconsistent. CONCLUSIONS: Our study provides high-level evidence for clinical and imaging features of CLOCC as well as associated disease entities. CLINICAL RELEVANCE STATEMENT: Our study provides high-level evidence on MRI features of CLOCC as well as a comprehensive list of disease entities potentially associated with CLOCC. Together, this will facilitate rigorous diagnostic workup of suspected CLOCC cases. KEY POINTS: ⢠Cytotoxic lesions of the corpus callosum (CLOCC) are a frequent MRI feature associated with various systemic diseases. ⢠Cytotoxic lesions of the corpus callosum show a highly homogenous MRI presentation and temporal dynamics. ⢠This comprehensive overview will benefit (neuro)radiologists during diagnostic workup.
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Corpo Caloso , Imageamento por Ressonância Magnética , Humanos , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Imageamento por Ressonância Magnética/métodos , COVID-19/complicações , COVID-19/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Neuroimagem/métodos , Diagnóstico DiferencialRESUMO
OBJECTIVE: This study was undertaken to provide a comprehensive review of neuroimaging characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A), a rare but severe neuroinflammatory disorder, to facilitate early diagnosis and appropriate treatment. METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis)-conforming systematic review and meta-analysis was performed on all available data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were extracted for both adult and paediatric forms. RESULTS: A total of 93 studies with 681 cases (55% males; median age = 46, range = 1-103 years) were included. Of these, 13 studies with a total of 535 cases were eligible for the meta-analysis. Clinically, GFAP-A was often preceded by a viral prodromal state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most common symptoms were headache, fever, and movement disturbances. Coexisting autoantibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities were also frequent (49%), most commonly manifesting as longitudinally extensive myelitis. There were 88 paediatric cases; they had less prominent neuroimaging findings with lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement (19%). CONCLUSIONS: This systematic review and meta-analysis provide high-level evidence for clinical and imaging phenotypes of GFAP-A, which will benefit the identification and clinical workup of suspected cases. Differential diagnostic cues to distinguish GFAP-A from common clinical and imaging mimics are provided as well as suitable magnetic resonance imaging protocol recommendations.
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Proteína Glial Fibrilar Ácida , Neuroimagem , Humanos , Astrócitos/patologia , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/imunologia , Proteína Glial Fibrilar Ácida/imunologia , Doenças Neuroinflamatórias/diagnóstico por imagem , Doenças Neuroinflamatórias/imunologia , FenótipoRESUMO
BACKGROUND: Due to the global increase in aging populations and changes in modern lifestyles, the prevalence of neurodegenerative diseases, cerebrovascular disorders, neuropsychiatrcic conditions, and related ailments is rising, placing an increasing burden on the global public health system. MATERIALS AND METHODS: All studies on tetramethylpyrazine (TMP) and its derivatives were obtained from reputable sources such as PubMed, Elsevier, Library Genesis, and Google Scholar. Comprehensive data on TMP and its derivatives was meticulously compiled. RESULTS: This comprehensive analysis explains the neuroprotective effects demonstrated by TMP and its derivatives in diseases of the central nervous system. These compounds exert their influence on various targets and signaling pathways, playing crucial roles in the development of various central nervous system diseases. Their multifaceted mechanisms include inhibiting oxidative damage, inflammation, cell apoptosis, calcium overload, glutamate excitotoxicity, and acetylcholinesterase activity. CONCLUSION: This review provides a brief summary of the most recent advancements in research on TMP and its derivatives in the context of central nervous system diseases. It involves synthesizing analogs of TMP and evaluating their effectiveness in models of central nervous system diseases. The ultimate goal is to facilitate the practical application of TMP and its derivatives in the future treatment of central nervous system diseases.
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Doenças do Sistema Nervoso Central , Neuroproteção , Humanos , Acetilcolinesterase , Doenças do Sistema Nervoso Central/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêuticoRESUMO
Central nervous system (CNS) diseases encompass spinal cord injuries, brain tumors, neurodegenerative diseases, and ischemic strokes. Recently, there has been a growing global recognition of CNS disorders as a leading cause of disability and death in humans and the second most common cause of death worldwide. The global burdens and treatment challenges posed by CNS disorders are particularly significant in the context of a rapidly expanding global population and aging demographics. The blood-brain barrier (BBB) presents a challenge for effective drug delivery in CNS disorders, as conventional drugs often have limited penetration into the brain. Advances in biomimetic membrane nanomaterials technology have shown promise in enhancing drug delivery for various CNS disorders, leveraging properties such as natural biological surfaces, high biocompatibility and biosafety. This review discusses recent developments in biomimetic membrane materials, summarizes the types and preparation methods of these materials, analyzes their applications in treating CNS injuries, and provides insights into the future prospects and limitations of biomimetic membrane materials.
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Materiais Biomiméticos , Barreira Hematoencefálica , Doenças do Sistema Nervoso Central , Sistemas de Liberação de Medicamentos , Materiais Biomiméticos/química , Humanos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Animais , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Membranas ArtificiaisRESUMO
INTRODUCTION: Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrates in the exocrine glands. Carpal tunnel syndrome (CTS) is suggested to be more frequent among SS patients than in the general population. The aim of this study was to seek associations between the CTS and the laboratory and clinical findings of SS patients. METHODS: Fifty patients diagnosed with primary SS (pSS) were examined. Clinical evaluation by a rheumatologist and electrophysiological studies were conducted. Data on laboratory tests results was collected. Control group consisted of 50 sex and age-matched individuals with osteoarthritis (OA). RESULTS: Out of 50 patients in the study group 27 (54%) were diagnosed with CTS. The prevalence of CTS among 50 individuals in the control group was 8%. Among pSS patients with CTS the joint involvement was not more common than in those from the non-CTS group [15 vs. 13 (p = 0.945)]. There was an expected difference in sleep disorders [18 vs. 9 (p = 0.012)] and paresthesia [23 vs. 13 (p = 0.024)]. The major finding was a significant difference in elevated beta2-microglobulin (B2MG) [23 vs. 13 (p = 0.024)]. Other studied factors, suggested in the literature as significant in the pSS-related neuropathy, were not statistically different between the groups. CONCLUSION: Our study confirms that CTS is more prevalent among pSS patients than in the general population and suggests that a new approach is required towards the pathogenesis of this phenomenon. We hypothesize that CTS is more associated with an overall disease activity than joint involvement as such.
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BACKGROUND: Cardiovascular, respiratory, and nervous system diseases have high morbidity and mortality rates, but the causal relationship between air pollution and these diseases remains controversial. METHODS: We conducted a large-scale genome-wide association (GWAS) study using Mendelian randomization (MR) to investigate the association between air pollution like Nitrogen dioxide (NO2), Nitrogen oxides (NOX), Particulate matter with diameter<2.5µm (PM2.5), Particulate matter with diameter<10µm (PM10) and cardiovascular, respiratory, and nervous system diseases, including acute myocardial infarction, heart failure, asthma, chronic obstructive pulmonary disease (COPD), pneumonia, stroke and Parkinson's disease. This study included 337,199 patients with acute myocardial infarction, 178,726 patients with heart failure, 463,010 patients with asthma, 462,933 patients with COPD, 486,484 patients with pneumonia, 484,598 patients with stroke, and 482,730 patients with Parkinson's disease. All genetic tools were identified from GWAS. The association effects of environmental pollution and these diseases were investigated using MR analysis, sensitivity analysis with heterogeneity, pleiotropy test, and leave-one-out test. RESULTS: Our MR analysis showed the association between NOX and the development of COPD and stroke (Odds ratio (OR)=1.010, 95â¯% Confidence interval (CI): 1.000ï½1.020, P=0.046; OR=1.017, 95â¯%CI:1.003-1.031, P=0.019), the association between PM2.5 and the development of asthma, COPD and stroke (OR=1.013, 95â¯%CI:1.003-1.024, P=0.011; OR=1.010, 95â¯%CI:1.000-1.019, P=0.035; OR=1.019, 95â¯%CI:1.004-1.033, P=0.012). No significant associations were found between the rest of the air pollution exposures and diseases. Leave-one-out sensitivity analysis showed stable results. CONCLUSIONS: The study clarifies the relationship between air pollution and cardiovascular, respiratory, and nervous system diseases, providing valuable evidence for environmental pollution prevention and population health monitoring, and provides a clear direction and evidence for the subsequent investigation of the association between air pollution and diseases.
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BACKGROUND: The burden of migraine goes beyond the pain and associated symptoms. We aimed to describe the impact of migraine in healthcare resource utilization (HCRU), work productivity, and mood disorders, as well as its economic cost. METHODS: Case-control study nested in a cross-sectional analysis of patient-reported data collected between 30/12/2019 and 20/04/2020 as part of the National Health and Wellness Survey, from respondents located in Spain. Adults (≥ 18 years old) who reported a physician diagnosis of migraine and ≥ 1 monthly headache days (MHD) in the previous 30 days were included. HCRU, health-related quality-of-life, depression scores, work and activity impairment, and the associated direct and indirect costs were assessed for four cohorts of migraine patients, according to the frequency of headache (MHD: 1-3, 4-7, 8-14, ≥ 15) and compared to a no-migraine control, matched to migraine cases by a propensity score based on demographic and clinical variables. RESULTS: The survey was completed by 595 people with active migraine, of whom 461 (77.4%) experienced < 8 MHDs and 134 (22.6%) ≥ 8 MHDs, and 1,190 non-migraine matched controls. Migraine patients presented worse mental and physical health functioning (SF-12 MCS: 41.9 vs. 44.7, p < 0.001; SF-12 PCS: 48.6 vs. 51.5, p < 0.001), worse self-reported health (EQ-5D VAS: 65.8 vs. 73.5, p < 0.001), more severe depression (PHQ-9: 8.9 vs. 6.1, p < 0.001), and higher overall work impairment (WPAI: 41.4 vs. 25.5, p < 0.001). People with migraine had higher HCRU, twice higher hospitalization rates (17.0% vs. 8.3%, p < 0.001) and 1.6 higher emergency room (ER) visit rates (51.4% vs. 31.2%, p < 0.001). Having migraine translated into higher annual costs with HCRU (894 vs. 530) and productivity losses (8,000 vs. 4,780) per person. Respondents with more MHDs presented worse outcomes and higher costs but suffering from 1-3 MHD also increased costs by 51.3%. CONCLUSIONS: Having migraine not only causes a massive impact on patients' quality of life and ability to work, but it also generates considerable economic costs for society. In Spain, having migraine was associated to 1.7 higher costs per patient. The clinical and economic burden increases with the frequency of headaches but is higher than controls even in patients suffering from 1-3 MHD.
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Estresse Financeiro , Transtornos de Enxaqueca , Adulto , Humanos , Adolescente , Espanha/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Qualidade de Vida , Transtornos de Enxaqueca/epidemiologia , Cefaleia , Efeitos Psicossociais da DoençaRESUMO
CONTEXT: Diabetic peripheral neuropathy (DPN) results in an enormous burden and reduces the quality of life for patients. Considering there is no specific drug for the management of DPN, traditional Chinese medicine (TCM) has increasingly drawn attention of clinicians and researchers around the world due to its characteristics of multiple targets, active components, and exemplary safety. OBJECTIVE: To summarize the current status of TCM in the treatment of DPN and provide directions for novel drug development, the clinical effects and potential mechanisms of TCM used in treating DPN were comprehensively reviewed. METHODS: Existing evidence on TCM interventions for DPN was screened from databases such as PubMed, the Cochrane Neuromuscular Disease Group Specialized Register (CENTRAL), and the Chinese National Knowledge Infrastructure Database (CNKI). The focus was on summarizing and analyzing representative preclinical and clinical TCM studies published before 2023. RESULTS: This review identified the ameliorative effects of about 22 single herbal extracts, more than 30 herbal compound prescriptions, and four Chinese patent medicines on DPN in preclinical and clinical research. The latest advances in the mechanism highlight that TCM exerts its beneficial effects on DPN by inhibiting inflammation, oxidative stress and apoptosis, endoplasmic reticulum stress and improving mitochondrial function. CONCLUSIONS: TCM has shown the power latent capacity in treating DPN. It is proposed that more large-scale and multi-center randomized controlled clinical trials and fundamental experiments should be conducted to further verify these findings.
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Neuropatias Diabéticas , Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Humanos , Neuropatias Diabéticas/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Qualidade de Vida , Estresse Oxidativo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodosRESUMO
Phosphodiesterase (PDE) hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and involve in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synaptogenesis, synaptic transmission, memory formation and cognitive function by catalyzing the hydrolysis of intracellular cAMP and cGMP. A large number of basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms; and also resist the occurrence and development of Parkinson's disease by reducing the cytotoxicity induced by α-syn and increasing the effect of miR-124-3p on cell activity. Alteration of PDE4 activity is the molecular basis of psychosis and cognitive disorders, therefore it is considered as one of the therapeutic targets for schizophrenia. PDE4 inhibitors play a role in depression; Autism spectrum and Huntington's disease by inhibiting the advanced glycation end product receptor (RAGE), TLR4 and NLRP3 pathways in the hippocampus, reducing the activation of microglia and the production of interleukin-1ß, down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors and Increase the nociception threshold. PDE4 inhibitors might be used in treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein (FMRP). PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination, which has potential in the treatment of multiple sclerosis. PDE4 also related to Bipolar disorder which may be one of the therapeutic targets. At present, several PDE4 inhibitors are on clinical trials for treatment of CNS diseases. This article reviews and discusses the progress on basic researches and clinical trials of PDE4 inhibitors in CNS diseases, providing reference for the prevention and treatment of CNS diseases and the development of new drugs.
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Polypyrimidine tract-binding protein 1 (PTBP1) is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, which plays a key role in alternative splicing of precursor mRNA and RNA metabolism. PTBP1 is universally expressed in various tissues and binds to multiple downstream transcripts to interfere with physiological and pathological processes such as the tumor growth, body metabolism, cardiovascular homeostasis, and central nervous system damage, showing great prospects in many fields. The function of PTBP1 involves the regulation and interaction of various upstream molecules, including circular RNAs (circRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These regulatory systems are inseparable from the development and treatment of diseases. Here, we review the latest knowledge regarding the structure and molecular functions of PTBP1 and summarize its functions and mechanisms of PTBP1 in various diseases, including controversial studies. Furthermore, we recommend future studies on PTBP1 and discuss the prospects of targeting PTBP1 in new clinical therapeutic approaches.
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INTRODUCTION: The internal representation of verticality could be disturbed when a lesion in the central nervous system (CNS) affects the centers where information from the vestibular, visual, and/or somatosensory systems, increasing the risk of falling. OBJECTIVE: The aim was to evaluate the vestibular and somatosensory contribution to the verticality pattern in patients with stroke and other neurological disorders. METHODS: A literature search was performed in PubMed, Scopus, Web of Science, and CINAHL databases. Cross-sectional, case-control, and cohort studies comparing body verticality in patients with stroke or CNS diseases (CNSD) versus healthy controls were selected. Subjective postural vertical (SPV) in roll and pitch planes was used as the primary variable. RESULTS: Ten studies reporting data from 390 subjects were included. The overall effect for CNSD patients showed a misperception of body verticality in roll (standardized mean difference [SMD] = 1.05; 95% confidence interval [CI] .84-1.25) and pitch planes (SMD = 1.03; 95% CI .51-1.55). In subgroup analyses, a high effect was observed in the perception of SPV both in roll and pitch planes in stroke (p = .002) and other CNSD (p < .001). CONCLUSION: These findings suggest a potential misperception of SPV in patients with stroke and other neurological disturbances. Patients with CNSD could present an alteration of vestibular and somatosensory contribution to verticality construction, particularly stroke patients with pusher syndrome (PS), followed by those with PS combined with hemineglect.
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Transtornos da Percepção , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Transtornos da Percepção/fisiopatologia , Transtornos da Percepção/etiologia , Propriocepção/fisiologia , Percepção Espacial/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologiaRESUMO
INTRODUCTION: Psychiatric comorbidities have a significant impact on patients' quality of life and often go undetected in neurologic practice. The aim of this study was to describe and characterize psychiatric comorbidities among patients hospitalized due to a neurologic disorder in mainland Portugal. METHODS: A retrospective observational study was performed by analyzing hospitalization with a primary diagnosis of neurologic disorder defined as categories 76, 77, 79 - 85, 95, 109 of the Clinical Classification Software for International Classification of Diseases, Ninth Revision, Clinical Modification, occurring between 2008 and 2015 in adult patients (≥ 18 years of age). Psychiatric comorbidities were determined as the presence of a secondary diagnosis belonging to the Clinical Classification Software categories 650 to 670. RESULTS: A total of 294 806 hospitalization episodes with a primary diagnosis of a neurologic disorder were recorded in adult patients between 2008 - 2015 in Portuguese public hospitals. Approximately 26.9% (n = 79 442) of the episodes had a recorded psychiatric comorbidity (22.1%; 32.2%, female versus male hospitalizations). Patients with registered psychiatric comorbidities were younger (66.2 ± 16.2 vs 68.6 ± 17.2 with no psychiatric comorbidities, p < 0.001), presented lower all-cause in-hospital mortality rates, and significantly longer mean hospital stays. 'Delirium, dementia, amnestic and other cognitive disorders' were recorded in 7.4% (n = 21 965) of the hospitalizations, followed by alcohol-related disorders in 6.5% (n = 19 302) and mood disorders in 6.1% (n = 18 079). Epilepsy/seizures were the neurologic disorders with the highest proportion of recorded psychiatric comorbidities (39.9%). CONCLUSION: Psychiatric comorbidities were recorded in more than a quarter of the hospitalizations with a primary diagnosis of a Neurologic disorder. Psychiatric comorbidities varied among neurological disorders and were associated with different demographic and clinical features.