RESUMO
Parkinson's disease (PD) is a common neurodegenerative disease. Here, the purpose of the study was to explore the function of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) in PD and its underlying mechanism. An in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-hydrochloride (MPTP)-induced mouse model of PD was generated and the SH-SY5Y cells were treated with MPP + to induce neuronal damage in vitro. Quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot were used to detect the expression of HOTAIR, miR-221-3p, α-synuclein and apoptosis-related genes. MTT, flow cytometry and TUNEL assay was used to detect cell viability and apoptosis, respectively. The levels of inflammatory cytokines TNF-α,IL-1ß and IL-6 were detected by ELISA assay. The levels of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and superoxide dismutase (SOD) were determined using the appropriate assay kits. The interactions between miR-221-3p and HOTAIR or α-synuclein were determined by dual luciferase assay and RNA binding protein immunoprecipitation (RIP). Co-localization of HOTAIR and miR-221-3p was also proved by immunofluorescence staining. The results showed that HOTAIR was highly expressed, while miR-221-3p expression was decreased in PD model in vivo and in vitro. In SH-SY5Y cells treated with MPP+, the knockdown of HOTAIR increased cell viability and reduced cell apoptosis, the secretion of inflammatory cytokines and oxidative stress reaction, while HOTAIR overexpression led to opposite effects. Furthermore, HOTAIR sponged miR-221-3p which directly targeted α-synuclein and thus regulated the expression of α-synuclein. Meanwhile, inhibiting miR-221-3p could partially reverse the neuroprotective effects of HOTAIR knockdown. In conclusion, HOTAIR attenuated the injury of SH-SY5Y cells induced by MPP+ via miR-221-3p/α-synuclein axis, suggesting the potential therapeutic value of HOTAIR in PD.
Assuntos
MicroRNAs , Doenças Neurodegenerativas , Doença de Parkinson , RNA Longo não Codificante/metabolismo , alfa-Sinucleína/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologiaRESUMO
KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (KNa1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF) variants, are associated with multiple epileptic disorders which are often refractory to conventional anti-seizure medications and summarized as KCNT1-related epilepsy. Although the detailed pathogenic mechanisms of KCNT1-related epilepsy remain unknown, increasing studies attempt to find effective medications for those patients by utilizing quinidine to inhibit hyperexcitable KNa1.1. However, it has been shown that controversial outcomes among studies and partial success in some individuals may be due to multiple factors, such as poor blood-brain barrier (BBB) penetration, mutation-dependent manner, phenotype-genotype associations, and rational therapeutic schedule. In recent years, with higher resolution of KNa1.1 structure in different activation states and advanced synthetic techniques, it improves the process performance of therapy targeting at KNa1.1 channel to achieve more effective outcomes. Here, we systematically reviewed the study history of quinidine on KCNT1-related epilepsy and its corresponding therapeutic effects. Then, we analyzed and summarized the possible causes behind the different outcomes of the application of quinidine. Finally, we outlooked the recent advances in precision medicine treatment for KCNT1-related epilepsy.
Assuntos
Epilepsia , Quinidina , Humanos , Quinidina/uso terapêutico , Anticonvulsivantes/uso terapêutico , Canais de Potássio Ativados por Sódio/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Canais de Potássio/genética , Canais de Potássio/uso terapêutico , Mutação , Proteínas do Tecido Nervoso/genéticaRESUMO
Ischemic stroke is one of the major causes of morbidity and mortality, affecting millions of people worldwide. Inevitably, the interruption of cerebral blood supply after ischemia may promote a cascade of pathophysiological processes. Moreover, the subsequent restoration of blood flow and reoxygenation may further aggravate brain tissue injury. Although recombinant tissue plasminogen activator (rt-PA) is the only approved therapy for restoring blood perfusion, the reperfusion injury and the narrow therapeutic time window restrict its application for most stroke patients. Increasing evidence indicates that multiple cell death mechanisms are relevant to cerebral ischemia-reperfusion injury, including apoptosis, necrosis, necroptosis, autophagy, pyroptosis, ferroptosis, and so on. Therefore, it is crucial to comprehend various cell death mechanisms and their interactions. In this review, we summarize the various signaling pathways underlying cerebral ischemia-reperfusion injury and elaborate on the crosstalk between the different mechanisms.
Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Humanos , Ativador de Plasminogênio Tecidual , Traumatismo por Reperfusão/tratamento farmacológico , Morte Celular , Necrose/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismoRESUMO
BACKGROUND: Treatment of major depression disorder with Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), during pregnancy effects on the neurological trajectory of the offspring and induces enduring consequences, notably emotional and cognitive impairment. The associations between prenatal exposure to SSRIs and neurological underpinnings of these atypical behaviors in offspring are contentious and poorly understood. METHODS: We examined modifications in physiological, morphological, and biochemical characteristics in male and female offspring of C57BL/6 exposed to CTM during the third trimester of gestation. We utilized different behavior procedures to observe depression and anxiety-like behavior in 1~2 month old CTM-exposed mouse offspring. We employed Golgi-Cox staining to examine the neuronal structure of medial prefrontal cortex (mPFC) in CTM-exposed mice following protein expression levels by utilizing biochemical techniques. RESULTS: Our results indicate an impaired behavior such as anxiety and altered locomotion along with the substantial reduction in dendritic length and the number of dendritic branches in CTM-exposed mice. We observed differentially increase c-Fos expression in the mPFC following altered protein expression levels relative to controls. CONCLUSIONS: Our finding supports the function of CTM as a prenatal modulator of susceptibility to depressive-like behavior in offspring. We indicate that prenatal CTM exposure elicits a negative impact on the central nervous system, especially those regions involved in cognition and drug reinforcement. Furthermore, genetic, chemo-genetic, and optogenetic methods should be used to explain the function of SSRIs such as CTM during pregnancy in the regulation of mood and emotion-related behaviors in children.
Assuntos
Transtorno Depressivo Maior , Efeitos Tardios da Exposição Pré-Natal , Animais , Ansiedade/induzido quimicamente , Citalopram/farmacologia , Depressão/induzido quimicamente , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
BACKGROUND: Chemokine levels in severe coronavirus disease 2019 (COVID-19) patients have been shown to be markedly elevated. But the role of chemokines in mild COVID-19 has not yet been established. According to the epidemiological statistics, most of the COVID-19 cases in Shiyan City, China, have been mild. The purpose of this study was to evaluate the level of chemokines in mild COVID-19 patients and explore the correlation between chemokines and host immune response. METHODS: In this study, we used an enzyme-linked immunosorbent assay to detect serum levels of chemokines in COVID-19 patients in Shiyan City. Expression of chemokine receptors and of other signaling molecules was measured by real-time polymerase chain reaction. RESULTS: We first demonstrated that COVID-19 patients, both sever and mild cases, are characterized by higher level of chemokines. Specifically, monocyte chemotactic protein 1 (MCP-1) is expressed at higher levels both in severe and mild cases of COVID-19. The receptor of MCP-1, C-C chemokine receptor type 2, was expressed at higher levels in mild COVID-19 patients. Finally, we observed a significant negative correlation between expression levels of interferon (IFN) regulatory factor 3 (IRF3) and serum levels of MCP-1 in mild COVID-19 patients. CONCLUSION: Higher expression of MCP-1 in mild COVID-19 patients might be correlated with inhibition of IFN signaling. The finding adds to our understanding of the immunopathological mechanisms of severe acute respiratory syndrome coronavirus 2 infection and provides potential therapeutic targets and strategies.
Assuntos
COVID-19/imunologia , Quimiocina CCL2/sangue , Quimiocinas/sangue , Interferon Tipo I/metabolismo , Adulto , COVID-19/metabolismo , COVID-19/fisiopatologia , China , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Fator Regulador 3 de Interferon/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores CCR2/sangue , Transdução de Sinais/imunologiaRESUMO
Glioblastoma is the most aggressive primary brain tumor in adults. The prognosis of patients with primary glioblastoma treated with the current standard of care, tumor resection followed by radiation therapy and auxiliary temozolomide, remains poor. Integrative genomic analyses have identified essential core signaling pathways and frequent genetic aberrations, which provide potential drug targets for glioblastoma treatment. Drugs against these therapeutic targets have been developed rapidly in recent years. Although some have shown promising effects on models in preclinical studies, many have shown only modest efficacy in clinical trials. New therapeutic strategies and potent drugs are urgently needed to improve the prognosis of patients with glioblastoma. The goal of this review is to summarize the current advances in drug development for targeted glioblastoma therapies and to reveal the major challenges encountered in clinical trials or treatment. This study will provide new perspectives for future studies of targeted therapeutic drug development and provide insights into the clinical treatment of glioblastoma.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Desenvolvimento de Medicamentos , Glioblastoma/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , PrognósticoRESUMO
BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.
Assuntos
Doença de Alzheimer , Demência Vascular , China , Cognição , Demência Vascular/tratamento farmacológico , Método Duplo-Cego , Humanos , Indanos/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Resultado do TratamentoRESUMO
A novel coronavirus disease, designated as COVID-19, has become a pandemic worldwide. This study aims to estimate the incubation period and serial interval of COVID-19. We collected contact tracing data in a municipality in Hubei province during a full outbreak period. The date of infection and infector-infectee pairs were inferred from the history of travel in Wuhan or exposed to confirmed cases. The incubation periods and serial intervals were estimated using parametric accelerated failure time models, accounting for interval censoring of the exposures. Our estimated median incubation period of COVID-19 is 5.4 days (bootstrapped 95% confidence interval (CI) 4.8-6.0), and the 2.5th and 97.5th percentiles are 1 and 15 days, respectively; while the estimated serial interval of COVID-19 falls within the range of -4 to 13 days with 95% confidence and has a median of 4.6 days (95% CI 3.7-5.5). Ninety-five per cent of symptomatic cases showed symptoms by 13.7 days (95% CI 12.5-14.9). The incubation periods and serial intervals were not significantly different between male and female, and among age groups. Our results suggest a considerable proportion of secondary transmission occurred prior to symptom onset. And the current practice of 14-day quarantine period in many regions is reasonable.
Assuntos
Infecções por Coronavirus/transmissão , Período de Incubação de Doenças Infecciosas , Pneumonia Viral/transmissão , Adolescente , Adulto , Idoso , COVID-19 , Criança , China/epidemiologia , Busca de Comunicante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Adulto JovemRESUMO
Explosive growth in the study of microbial epigenetics has revealed a diversity of chemical structures and biological functions of DNA modifications in restriction-modification (R-M) and basic genetic processes. Here, we describe the discovery of shared consensus sequences for two seemingly unrelated DNA modification systems, 6mA methylation and phosphorothioation (PT), in which sulfur replaces a nonbridging oxygen in the DNA backbone. Mass spectrometric analysis of DNA from Escherichia coli B7A and Salmonella enterica serovar Cerro 87, strains possessing PT-based R-M genes, revealed d(GPS6mA) dinucleotides in the GPS6mAAC consensus representing â¼5% of the 1,100 to 1,300 PT-modified d(GPSA) motifs per genome, with 6mA arising from a yet-to-be-identified methyltransferase. To further explore PT and 6mA in another consensus sequence, GPS6mATC, we engineered a strain of E. coli HST04 to express Dnd genes from Hahella chejuensis KCTC2396 (PT in GPSATC) and Dam methyltransferase from E. coli DH10B (6mA in G6mATC). Based on this model, in vitro studies revealed reduced Dam activity in GPSATC-containing oligonucleotides whereas single-molecule real-time sequencing of HST04 DNA revealed 6mA in all 2,058 GPSATC sites (5% of 37,698 total GATC sites). This model system also revealed temperature-sensitive restriction by DndFGH in KCTC2396 and B7A, which was exploited to discover that 6mA can substitute for PT to confer resistance to restriction by the DndFGH system. These results point to complex but unappreciated interactions between DNA modification systems and raise the possibility of coevolution of interacting systems to facilitate the function of each.
Assuntos
Metilação de DNA , DNA Bacteriano/genética , Epigenômica , Escherichia coli/genética , Genoma Bacteriano , Deleção de Genes , Regulação Bacteriana da Expressão Gênica/fisiologia , Viabilidade Microbiana/genéticaRESUMO
Ongoing studies have determined that the gut microbiota is a major factor influencing both health and disease. Host genetic factors and environmental factors contribute to differences in gut microbiota composition and function. Intestinal dysbiosis is a cause or a contributory cause for diseases in multiple body systems, ranging from the digestive system to the immune, cardiovascular, respiratory, and even nervous system. Investigation of pathogenesis has identified specific species or strains, bacterial genes, and metabolites that play roles in certain diseases and represent potential drug targets. As research progresses, gut microbiome-based diagnosis and therapy are proposed and applied, which might lead to considerable progress in precision medicine. We further discuss the limitations of current studies and potential solutions.
Assuntos
Doença , Microbioma Gastrointestinal , Saúde , Transplante de Microbiota Fecal , Humanos , Terapia de Alvo Molecular , Transdução de SinaisRESUMO
Antibiotic production is often governed by large gene clusters composed of genes related to antibiotic scaffold synthesis, tailoring, regulation, and resistance. With the expansion of genome sequencing, a considerable number of antibiotic gene clusters has been isolated and characterized. The emerging genome engineering techniques make it possible towards more efficient engineering of antibiotics. In addition to genomic editing, multiple synthetic biology approaches have been developed for the exploration and improvement of antibiotic natural products. Here, we review the progress in the development of these genome editing techniques used to engineer new antibiotics, focusing on three aspects of genome engineering: direct cloning of large genomic fragments, genome engineering of gene clusters, and regulation of gene cluster expression. This review will not only summarize the current uses of genomic engineering techniques for cloning and assembly of antibiotic gene clusters or for altering antibiotic synthetic pathways but will also provide perspectives on the future directions of rebuilding biological systems for the design of novel antibiotics.
Assuntos
Antibacterianos , Engenharia Genética/métodos , Biologia Sintética/métodos , Animais , HumanosRESUMO
OBJECTIVES: The clinical and epidemiological profiles of Guillain-Barré syndrome (GBS) in southern China have yet to be fully recognised. We aimed to investigate the subtypes of GBS in southern China, compare the clinical features of demyelinating form with that of axonal form and test whether preceding infections and age have influence on the clinical phenotype, disease course and severity of GBS. METHODS: Medical records of patients with a diagnosis of GBS admitted to 31 tertiary hospitals, located in 14 provinces in southern China, from 1 January 2013 to 30 September 2016, were collected and retrospectively reviewed. RESULTS: Finally. 1056 patients, including 887 classic GBS and 169 variants, were enrolled. The 661 classic patients with available electromyographic data were grouped as having acute inflammatory demyelinating polyneuropathy (AIDP, 49.0%), acute motor axonal neuropathy (AMAN, 18.8%), inexcitable (0.9%) and equivocal (31.3%). In contrast to AIDP, patients with AMAN were characterised by earlier nadir (P=0.000), higher Hughes score at nadir (P=0.003) and at discharge (P=0.000). Preceding upper respiratory infections were identified in 369 (34.9%) patients, who were more inclined to develop AIDP (P=0.000) and Miller-Fisher syndrome (P=0.027), whereas gastrointestinal infection were found in 89 (8.4%) patients, who were more prone to develop AMAN (P=0.000), with more severe illness (P=0.001) and longer hospital stay (P=0.009). Children (≤15 years) and the elderly (≥56 years) were more severe at nadir, the elderly had the longest hospital stay (P=0.023). CONCLUSION: AIDP is the predominant form in southern China, which is different from data of northern China. The different subtypes, preceding infection and age of onset can partially determine the disease progression, severity and short-term recovery speed of GBS. CLINICAL TRIAL REGISTRATION: ChiCTR-RRC-17014152.
Assuntos
Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China , Feminino , Síndrome de Guillain-Barré/fisiopatologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
Early diagnosis plays a pivotal role in handling the global health challenge posed by liver diseases. However, early-stage lesions are typically quite small, presenting significant difficulties due to insufficient regions for developing effective features, indistinguishable boundaries of small lesions, and a lack of tiny liver lesion masks. To address these issues, we approach the solution in two-fold: an efficient model and a high-quality dataset. The model is built upon the advantages of path signature and camouflaged object detection. The path signature narrows down the ambiguous boundaries between lesions and other tissues while the camouflaged object detection achieves high accuracy in detecting inconspicuous lesions. The two are seamlessly integrated to ensure high accuracy and fidelity. For the dataset, we collect more than ten thousand liver images with over four thousand lesions, approximately half of which are small. Experiments on both an established dataset and our newly constructed one show that the proposed model outperforms state-of-the-art semantic segmentation and camouflaged object detection models, particularly in detecting small lesions. Moreover, the decisive and faithful salience maps generated by the model at the boundary regions demonstrate its strong robustness.
Assuntos
Interpretação de Imagem Assistida por Computador , Fígado , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Interpretação de Imagem Assistida por Computador/métodos , Algoritmos , Neoplasias Hepáticas/diagnóstico por imagem , Bases de Dados Factuais , Imageamento por Ressonância Magnética/métodosRESUMO
The commensal microbiota of the mosquito gut plays a complex role in determining the vector competence for arboviruses. In this study, we identified a bacterium from the gut of field Aedes albopictus mosquitoes named Rosenbergiella sp. YN46 (Rosenbergiella_YN46) that rendered mosquitoes refractory to infection with dengue and Zika viruses. Inoculation of 1.6 × 103 colony forming units (CFUs) of Rosenbergiella_YN46 into A. albopictus mosquitoes effectively prevents viral infection. Mechanistically, this bacterium secretes glucose dehydrogenase (RyGDH), which acidifies the gut lumen of fed mosquitoes, causing irreversible conformational changes in the flavivirus envelope protein that prevent viral entry into cells. In semifield conditions, Rosenbergiella_YN46 exhibits effective transstadial transmission in field mosquitoes, which blocks transmission of dengue virus by newly emerged adult mosquitoes. The prevalence of Rosenbergiella_YN46 is greater in mosquitoes from low-dengue areas (52.9 to ~91.7%) than in those from dengue-endemic regions (0 to ~6.7%). Rosenbergiella_YN46 may offer an effective and safe lead for flavivirus biocontrol.
Assuntos
Aedes , Vírus da Dengue , Mosquitos Vetores , Simbiose , Zika virus , Animais , Aedes/microbiologia , Aedes/virologia , Vírus da Dengue/fisiologia , Mosquitos Vetores/virologia , Mosquitos Vetores/microbiologia , Zika virus/fisiologia , Dengue/transmissão , Dengue/virologia , Dengue/prevenção & controle , Microbioma Gastrointestinal , Acetobacteraceae/fisiologia , Feminino , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/genética , Flavivirus/fisiologia , Flavivirus/genética , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologiaRESUMO
Parkinson's disease is a neurodegenerative disorder, and ferroptosis plays a significant role in the pathological mechanism underlying Parkinson's disease. Rapamycin, an autophagy inducer, has been shown to have neuroprotective effects in Parkinson's disease. However, the link between rapamycin and ferroptosis in Parkinson's disease is not entirely clear. In this study, rapamycin was administered to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model and a 1-methyl-4-phenylpyridinium-induced Parkinson's disease PC12 cell model. The results showed that rapamycin improved the behavioral symptoms of Parkinson's disease model mice, reduced the loss of dopamine neurons in the substantia nigra pars compacta, and reduced the expression of ferroptosis-related indicators (glutathione peroxidase 4, recombinant solute carrier family 7, member 11, glutathione, malondialdehyde, and reactive oxygen species). In the Parkinson's disease cell model, rapamycin improved cell viability and reduced ferroptosis. The neuroprotective effect of rapamycin was attenuated by a ferroptosis inducer (methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahyyridoindole-3-carboxylate) and an autophagy inhibitor (3-methyladenine). Inhibiting ferroptosis by activating autophagy may be an important mechanism by which rapamycin exerts its neuroprotective effects. Therefore, the regulation of ferroptosis and autophagy may provide a therapeutic target for drug treatments in Parkinson's disease.
RESUMO
Mulberry leaf (ML) and mulberry leaf extract (MLE) have numerous biological properties, such as regulating sugar and lipid metabolism, reducing blood glucose, and increasing insulin secretion. The aim of this study was to perform a systematic review and meta-analysis of randomized clinical trials to examine the effect of ML/MLE supplementation on glycemic traits in adults, including fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), and fasting plasma insulin (FPI). Twelve clinical trials (615 participants) fulfilled the eligibility criteria for the present meta-analysis, which included sensitivity analysis and GRADE (grading of recommendations assessment, development, and evaluation) certainty. Based on the heterogeneity between included studies, a random effects model was applied in the meta-analysis, and the results are expressed as WMD (weighted mean differences) with 95% CI (confidence intervals). Meta-analysis showed that ML/MLE supplementation resulted in a significant reduction in FBG by -0.47 mmol L-1, HbA1c by -2.92 mmol mol-1, and FPI by -0.58 µIU mL-1. In addition, subgroup analysis indicated that long-term supplementation of ML/MLE (≥8 weeks) was more effective for regulation of the glycemic traits in the non-healthy and baseline FPG >6.1 mmol L-1 subgroups. Glycemic regulation by ML/MLE may be attributed to the phytochemicals they contain, which are mainly 1-deoxynojirimycin, flavonoids, phenolics, and polysaccharides.
Assuntos
Diabetes Mellitus Tipo 2 , Morus , Adulto , Humanos , Glicemia/metabolismo , Hemoglobinas Glicadas , Morus/química , Frutas/química , Extratos Vegetais/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
Although potassium channelopathies have been linked to a wide range of neurological conditions, the underlying pathogenic mechanism is not always clear, and a systematic summary of clinical manifestation is absent. Several neurological disorders have been associated with alterations of calcium-activated potassium channels (KCa channels), such as loss- or gain-of-function mutations, post-transcriptional modification, etc. Here, we outlined the current understanding of the molecular and cellular properties of three subtypes of KCa channels, including big conductance KCa channels (BK), small conductance KCa channels (SK), and the intermediate conductance KCa channels (IK). Next, we comprehensively reviewed the loss- or gain-of-function mutations of each KCa channel and described the corresponding mutation sites in specific diseases to broaden the phenotypic-genotypic spectrum of KCa-related neurological disorders. Moreover, we reviewed the current pharmaceutical strategies targeting KCa channels in KCa-related neurological disorders to provide new directions for drug discovery in anti-seizure medication.
Assuntos
Doenças do Sistema Nervoso , Canais de Potássio Cálcio-Ativados , Humanos , Doenças do Sistema Nervoso/tratamento farmacológicoRESUMO
BACKGROUND: Metabolic acidosis plays a key role in transient global cerebral ischemiareperfusion (I/R) induced delayed neuronal death (DND) of the hippocampal CA1 region of gerbils. Na+ coupled HCO3 - transporters (NBCs) mediated Na+/HCO3- - co-transportation can be activated by the pH gradient of intracellular and extracellular environments induced by acidosis. However, whether NBCs are activated and involved in I/R-induced neuronal injury is unknown. OBJECTIVE: In this work, we studied neuronal apoptosis, astrocyte activation, and hippocampusdependent memory task using a well-established transient global cerebral I/R model of gerbils and investigated whether the specific NBCs inhibitor S0859 could reverse this injury. METHODS: To explore the role of S0859 in I/R-induced DND, we established a transient global cerebral I/R model of Mongolian gerbils and studied neuronal apoptosis by using Nissl stain and TUNEL assay. The excitability and NBCs current were analyzed by whole-cell patch-clamp, while the cognitive function was evaluated by Barnes maze. RESULTS: We found that I/R increased the NBCs current, inhibited the excitability of CA1 neurons, and led to apoptosis in CA1 neurons. Selective NBCs inhibitor S0859 protected CA1 neurons from I/R induced neuronal cell death, astrocyte accumulation, and spatial memory impairment. CONCLUSION: These findings indicate that NBCs mediate transient global cerebral I/R induced DND of CA1 neurons, and NBCs inhibitors could be a promising target to protect neuronal functions after I/R.
Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Simportadores , Animais , Gerbillinae/metabolismo , Simportadores/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Isquemia Encefálica/metabolismo , Região CA1 Hipocampal , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
Liver vessels generated from computed tomography are usually pretty small, which poses major challenges for satisfactory vessel segmentation, including 1) the scarcity of high-quality and large-volume vessel masks, 2) the difficulty in capturing vessel-specific features, and 3) the heavily imbalanced distribution of vessels and liver tissues. To advance, a sophisticated model and an elaborated dataset have been built. The model has a newly conceived Laplacian salience filter that highlights vessel-like regions and suppresses other liver regions to shape the vessel-specific feature learning and to balance vessels against others. It is further coupled with a pyramid deep learning architecture to capture different levels of features, thus improving the feature formulation. Experiments show that this model markedly outperforms the state-of-the-art approaches, achieving a relative improvement of Dice score by at least 1.63% compared to the existing best model on available datasets. More promisingly, the averaged Dice score produced by the existing models on the newly constructed dataset is as high as 0.734±0.070 , which is at least 18.3% higher than that obtained from the existing best dataset under the same settings. These observations suggest that the proposed Laplacian salience, together with the elaborated dataset, can be helpful for liver vessel segmentation.
Assuntos
Fígado , Tomografia Computadorizada por Raios X , Fígado/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodosRESUMO
AIMS: We performed cell and animal experiments to explore the therapeutic effect of artemisinin on Parkinson's disease (PD) and the TLR4/Myd88 signaling pathway. METHODS: C57 mice were randomly divided into the blank, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and artemisinin-treated groups. Clinical symptoms, the number of dopaminergic (DAergic) neurons in the substantia nigra, and microglial cell activation were compared among the three groups. Subsequently, BV-2 cell activation and TLR4/Myd88 pathway component expression were compared among the blank, MPP+ -treated, artemisinin-treated, and TLR4 activator-treated groups. RESULTS: Behavioral symptoms were improved, the number of DAergic neurons in the substantia nigra of the midbrain was increased, and microglial cell activation was decreased in artemisinin-treated MPTP-induced PD model mice compared with control-treated MPTP-induced PD model mice (p < 0.05). The cell experiments revealed that artemisinin treatment reduced MPP+ -induced BV-2 cell activation and inhibited the TLR4/Myd88 signaling pathway. Moreover, the effect of artemisinin on the BV-2 cell model was inhibited by the TLR4 activator LPS (p < 0.05). CONCLUSION: Artemisinin may reduce damage to DAergic neurons in a PD mouse model by decreasing microglial activation through the TLR4-mediated MyD88-dependent signaling pathway. However, this finding cannot explain the relationship between microglia and DAergic neurons.