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The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1H-NMR and 13Câ NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI50 values of 4.87±0.23â µM and 9.97±1.44â µM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC50 value of 0.135±0.041â µM, and its activity was approximately 1/3 of the positive control Palbociclib.
Assuntos
Antineoplásicos , Artemisininas , Neoplasias da Mama , Proliferação de Células , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Humanos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Artemisininas/farmacologia , Artemisininas/química , Artemisininas/síntese química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Feminino , Relação Dose-Resposta a Droga , Simulação de Acoplamento MolecularRESUMO
In air traffic control (ATC), speech communication with radio transmission is the primary way to exchange information between the controller and the pilot. As a result, the integration of automatic speech recognition (ASR) systems holds immense potential for reducing controllers' workload and plays a crucial role in various ATC scenarios, which is particularly significant for ATC research. This article provides a comprehensive review of ASR technology's applications in the ATC communication system. Firstly, it offers a comprehensive overview of current research, including ATC corpora, ASR models, evaluation measures and application scenarios. A more comprehensive and accurate evaluation methodology tailored for ATC is proposed, considering advancements in communication sensing systems and deep learning techniques. This methodology helps researchers in enhancing ASR systems and improving the overall performance of ATC systems. Finally, future research recommendations are identified based on the primary challenges and issues. The authors sincerely hope this work will serve as a clear technical roadmap for ASR endeavors within the ATC domain and make a valuable contribution to the research community.
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Drug delivery system (DDS) refers to the method of delivering drugs to the targeted sites with minimal risk. One popular strategy of DDS is using nanoparticles as a drug carrier, which are made from biocompatible and degradable polymers. Here, nanoparticles composed of Arthrospira-derived sulfated polysaccharide (AP) and chitosan were developed and expected to possess the capabilities of antiviral, antibacterial, and pH-sensitive properties. The composite nanoparticles, abbreviated as APC, were optimized for stability of morphology and size (~160 nm) in the physiological environment (pH = 7.4). Potent antibacterial (over 2 µg/mL) and antiviral (over 6.596 µg/mL) properties were verified in vitro. The pH-sensitive release behavior and release kinetics of drug-loaded APC nanoparticles were examined for various categories of drugs, including hydrophilic, hydrophobic, and protein drugs, under different pH values of the surroundings. Effects of APC nanoparticles were also evaluated in lung cancer cells and neural stem cells. The use of APC nanoparticles as a drug delivery system maintained the bioactivity of the drug to inhibit the proliferation of lung cancer cells (with ~40% reduction) and to relieve the growth inhibitory effect on neural stem cells. These findings indicate that the pH-sensitive and biocompatible composite nanoparticles of sulfated polysaccharide and chitosan well keep the antiviral and antibacterial properties and may serve as a promising multifunctional drug carrier for further biomedical applications.
Assuntos
Quitosana , Neoplasias Pulmonares , Nanopartículas , Humanos , Portadores de Fármacos/química , Quitosana/química , Antivirais , Sulfatos , Antibacterianos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Polissacarídeos , Nanopartículas/química , Liberação Controlada de Fármacos , Concentração de Íons de HidrogênioRESUMO
Diesel-fired combustion is one of the main sources of air pollution in the world. In this study, to better understand the energy consumption and main air pollutant emissions of diesel-fired combustion, a practical investigation and historical data analyses were conducted to determine the variations and driving forces of diesel consumption, the distribution of diesel consumption, and the contribution of emissions among various industries. Based on the results of this study, future control measures can be proposed for diesel-fired combustion. The results show that economic development led to an increase in the total volume of passengers and freight transportation, and the number of diesel vehicles increased from 0.16 million in 2009 to 0.25 million in 2018. However, diesel consumption in Beijing decreased from 2.4 Mt in 2009 to 1.8 Mt in 2018 due to the dominant driving forces, such as structural optimization of the diesel vehicle fleet and stricter limit standards for single-vehicle fuel consumption. The use of diesel vehicles in the logistics and transportation industries and the use of diesel-fired machinery in the construction industry were the two main sources of diesel consumption, accounting for 55% and 23% of the total, respectively. The main air pollutant emissions from diesel-fired combustion from 2009 to 2018 first increased and then decreased, while the NOX emissions peaked at 74,800 tons in 2014, which was affected by the structural optimization of the vehicle fleet and the elimination of old diesel trucks. The emissions finally decreased to 54,000 tons in 2018, which was approximately 89% of the amount in 2009. However, the continuously increasing contribution of diesel combustion to the total emissions requires more attention. The electrification of diesel vehicles and the structural upgrading of diesel vehicles have played important roles in mitigating the emissions of diesel combustion. Our study suggests that consumption control targets should be set, reduction plans for key industries such as the logistics and transportation, construction, and tourism industries should be developed, and low-emission zones should be created to promote the elimination and updating of low-emission diesel vehicles and machinery.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Ambientais , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Pequim , China , Monitoramento Ambiental , Gasolina , Veículos Automotores , Emissões de Veículos/análiseRESUMO
BACKGROUND: The yak is a species of livestock which is crucial for local communities of the Qinghai-Tibet Plateau and adjacent regions and naturally owns one more thoracic vertebra than cattle. Recently, a sub-population of yak termed as the Jinchuan yak has been identified with over half its members own a thoracolumbar vertebral formula of T15L5 instead of the natural T14L5 arrangement. The novel T15L5 positioning is a preferred genetic trait leading to enhanced meat and milk production. Selective breeding of this trait would have great agricultural value and exploration of the molecular mechanisms underlying this trait would both accelerate this process and provide us insight into the development and regulation of somitogenesis. RESULTS: Here we investigated the genetic background of the Jinchuan yak through resequencing fifteen individuals, comprising five T15L5 individuals and ten T14L5 individuals with an average sequencing depth of > 10X, whose thoracolumbar vertebral formulae were confirmed by anatomical observation. Principal component analysis, linkage disequilibrium analysis, phylogenetic analysis, and selective sweep analysis were carried out to explore Jinchuan yak's genetic background. Three hundred and thirty candidate markers were identified as associated with the additional thoracic vertebrae and target sequencing was used to validate seven carefully selected markers in an additional 51 Jinchuan yaks. The accuracies of predicting 15 thoracic vertebrae and 20 thoracolumbar vertebrae with these 7 markers were 100.00 and 33.33% despite they both could only represent 20% of all possible genetic diversity. Two genes, PPP2R2B and TBLR1, were found to harbour the most candidate markers associated with the trait and likely contribute to the unique somitic number and identity according to their reported roles in the mechanism of somitogenesis. CONCLUSIONS: Our findings provide a clear depiction of the Jinchuan yak's genetic background and a solid foundation for marker-assistant selection. Further exploitation of this unique population and trait could be promoted with the aid of our genomic resource.
Assuntos
Locos de Características Quantitativas , Somitos/crescimento & desenvolvimento , Vértebras Torácicas/anatomia & histologia , Sequenciamento Completo do Genoma/veterinária , Animais , Cruzamento , Bovinos , Heterogeneidade Genética , Desequilíbrio de Ligação , Fenótipo , Filogenia , TibetRESUMO
The yak (Bos grunniens), which is a unique bovine breed that is distributed mainly in the Qinghai-Tibetan Plateau, is considered a good model for studying plateau adaptability in mammals. The lungs are important functional organs that enable animals to adapt to their external environment. However, the genetic mechanism underlying the adaptability of yak lungs to harsh plateau environments remains unknown. To explore the unique evolutionary process and genetic mechanism of yak adaptation to plateau environments, we performed transcriptome sequencing of yak and cattle (Bos taurus) lungs using RNA-Seq technology and a subsequent comparison analysis to identify the positively selected genes in the yak. After deep sequencing, a normal transcriptome profile of yak lung that containing a total of 16,815 expressed genes was obtained, and the characteristics of yak lungs transcriptome was described by functional analysis. Furthermore, Ka/Ks comparison statistics result showed that 39 strong positively selected genes are identified from yak lungs. Further GO and KEGG analysis was conducted for the functional annotation of these genes. The results of this study provide valuable data for further explorations of the unique evolutionary process of high-altitude hypoxia adaptation in yaks in the Tibetan Plateau and the genetic mechanism at the molecular level.
Assuntos
Bovinos/genética , Pulmão/metabolismo , Seleção Genética , Transcriptoma , Altitude , Animais , Bovinos/metabolismo , Evolução Molecular , Perfilação da Expressão Gênica , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Anotação de Sequência Molecular , Análise de Sequência de RNARESUMO
BACKGROUND: Nicotine is known to differentially regulate cortical interneuron and pyramidal neuron activities in the neocortex, while the underlying molecular mechanisms have not been well studied. In this study, RNA-sequencing was performed in acutely isolated cortical somatostatin (Sst)- positive interneurons and pyramidal neurons (Thy1) from mice treated with systemic nicotine for 14 days. We assessed the differentially expressed genes (DEGs) by nicotine in Sst- or Thy1- neurons, respectively, and then compared DEGs between Sst- and Thy1- neurons in the absence and presence of nicotine. RESULTS: In Sst-neurons, the DEGs by nicotine were associated with glycerophospholipid and nicotinate and nicotinamide metabolism; while in Thy1-neurons those related to immune response and purine and pyrimidine metabolisms were affected. Under basal condition, the DEGs between Sst- and Thy1- neurons were frequently associated with signal transduction, phosphorylation and potassium channel regulation. However, some new DEGs between Sst- and Thy1- neurons were found after nicotine, the majority of which belong to mitochondrial respiratory chain complex. CONCLUSIONS: Nicotine differentially affected subset of genes in Sst- and Thy1- neurons, which might contribute to the distinct effect of nicotine on interneuron and pyramidal neuron activities. Meanwhile, the altered transcripts associated with mitochondrial activity were found between interneurons and pyramidal neurons after chronic nicotine.
Assuntos
Encéfalo/citologia , Perfilação da Expressão Gênica , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Nicotina/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Camundongos , Análise de Sequência de RNA , Fatores de TempoRESUMO
The present study explored the possible preventive effects of blue light emitting diodes (LEDs) on cadmium (Cd)-induced oxidative stress and immunotoxicity in zebrafish. To this end, zebrafish were exposed to a white fluorescent bulb or blue LEDs (LDB, peak at 450nm, at an irradiance of 0.9W/m2), and 0 or 30µgL-1 waterborne Cd for 5 weeks. Growth performance, survival rate, and hepatic histology, ultrastructure, antioxidant and innate immune responses were determined in zebrafish. Cd exposure alone reduced growth and survival rate, and induced oxidative damage and changes in histology and ultrastructure. However, Cd exposure in combination with LDB apparently relieved these negative effects. The alleviation of adverse effects might result from the up-regulation of antioxidant and innate immune genes at transcriptional, translational, or post-translational levels. Cd exposure alone dramatically enhanced mRNA levels of nuclear transcription factor κB (NF-κB) and E2-related factor (Nrf2). However, compared to Cd exposure alone, Cd exposure in combination with LDB apparently down-regulated both genes. Taken together, our results suggest that chronic Cd exposure induced a negative effect on zebrafish, possibly involved in NF-κB-induced immunotoxicity and Nrf2-induced oxidative stress. Finally, for the first time, our data demonstrated that LDB could protect fish against Cd toxicity.
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Antioxidantes , Cádmio/toxicidade , Imunidade Inata , Luz , Fígado/efeitos dos fármacos , Estresse Oxidativo , Peixe-Zebra/metabolismo , Animais , Antioxidantes/metabolismo , Regulação para Baixo , Exposição Ambiental , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Fígado/metabolismo , Fígado/patologia , Fígado/ultraestrutura , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Regulação para Cima , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Isocorydine and its analogs were extracted from Dicranostigma leptopodum and Stephania yunnanensis through the method of natural products chemistry. Its derivatives were prepared by chemical structure modifications from isocorydine. MTT method was used to study the inhibitory effect of those compounds on the growth of HepG2, HeLa and MGC-803 cancer cell lines in vitro. The results showed that isocorydine and its analogs all have the growth inhibition for those cancer cell lines. This paper investigated the structure-activity relationship of isocorydine and its derivatives with anticancer activity in the aspect of stereochemical structure, functional groups positions of the compounds and the electron density of aromatic rings based on the single crystal diffraction structure and the molecular docking of EGFR and isocorydine.
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Antineoplásicos/farmacologia , Aporfinas/farmacologia , Linhagem Celular Tumoral , Receptores ErbB , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We evaluated the effects of acute Zn exposure (4 and 8 mg L(-1) Zn) on lipid peroxidation, and activities and mRNA levels of antioxidant enzyme genes (Cu/Zn-SOD, CAT, GPx, and GR), and gene expression of the Nrf2-Keap1 signaling molecule at different exposure times (0, 6, 12, 24, 48, and 96 h) in the spleen of large yellow croaker. Lipid peroxidation remained relatively constant during 6-48 h and 6-24 h and sharply increased at 96 h and during 48-96 h in fish exposed to 4 and 8 mg L(-1) Zn, respectively. Activities of all tested enzymes increased during the early stage of exposure and decreased towards the end of the exposure in both groups. However, mRNA levels of antioxidant enzyme genes were dramatically up-regulated by 4 and 8 mg L(-1) Zn during the late stage of exposure. During the early stage of exposure for 6 h, the 8 mg L(-1) Zn exposure sharply increased mRNA levels of Cu/Zn-SOD, CAT, GPx1b, Nrf2, and Keap1, whereas, the 4 mg L(-1) Zn exposure did not significantly affect the expression of these genes. Our data also showed positive relationships between Nrf2 expression and mRNA levels of its target genes, suggesting that Nrf2 was required for the protracted induction of these genes. Furthermore, a sharp increase in Keap1 expression levels was observed in fish exposed to 4 mg L(-1) at 96 h, and 8 mg L(-1) at 6, 48, and 96 h. In conclusion, the present study demonstrated that Zn-induced antioxidant defenses were involved in modifications at enzymatic and transcriptional levels and the transcriptional regulation of the Nrf2-Keap1 signaling molecule; these results may contribute to the understanding of mechanisms that maintain the correct redox balance in the immune organ of the large yellow croaker.
Assuntos
Proteínas de Peixes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Perciformes/genética , Baço/efeitos dos fármacos , Zinco/toxicidade , Animais , Antioxidantes/metabolismo , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peroxidação de Lipídeos , Fator 2 Relacionado a NF-E2/metabolismo , Perciformes/imunologia , Perciformes/metabolismo , Baço/metabolismo , Poluentes Químicos da Água/toxicidadeRESUMO
The aim of the present study was to evaluate the effects of acute inorganic Hg exposure (0, 32 and 64µgHgL(-1)) on lipid peroxidation, activities and gene expression of antioxidant enzymes (Cu/Zn-SOD, CAT, GPx, GR and GST), and mRNA levels of the Keap1-Nrf2 signaling molecules at different exposure times (6h, 12h, 24h, 48h, and 96h) in the liver of large yellow croaker Pseudosciaena crocea. The results showed that lipid peroxidation was sharply reduced by 32µg Hg L(-1) during 6-12h before returning to control levels. Similarly, lipid peroxidation was significantly reduced during 6-12h followed by a sharp increase towards the end of the exposure in the 64µgHgL(-1) group. There was a negative relationship between lipid peroxidation and antioxidant enzyme activities, and positive relationship between activities and gene expression of antioxidant enzymes, suggesting that the changes at a molecular level may underlie enzymatic level and accordingly affect hepatic lipid peroxidation. Obtained results also showed a coordinated transcriptional regulation of antioxidant genes, suggesting that Nrf2 is required for the protracted induction of these genes. Furthermore, a negative relationship between the mRNA levels of Nrf2 and Keap1 indicated that Keap1 may play an important role in switching off the Nrf2 response. In conclusion, this is the first study to elucidate effects of waterborne Hg on antioxidant system in large yellow croaker through the Keap1-Nrf2 pathway, which will aid our understanding of the molecular mechanisms of waterborne heavy metal on antioxidant responses in fish.
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Mercúrio/toxicidade , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Perciformes/metabolismo , Animais , Antioxidantes/metabolismo , Regulação da Expressão Gênica , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mercúrio/metabolismo , Compostos de Mercúrio/metabolismo , Compostos de Mercúrio/toxicidade , Fator 2 Relacionado a NF-E2/genética , Oxirredução/efeitos dos fármacos , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacosRESUMO
AMP-activated protein kinase (AMPK) is a highly conserved and multi-functional protein kinase that plays important roles in both intracellular energy balance and cellular stress response. In the present study, molecular characterization, tissue distribution and gene expression levels of the AMPK α1 and α2 genes from turbot (Scophthalmus maximus) under salinity stress are described. The complete coding regions of the AMPK α1 and α2 genes were isolated from turbot through degenerate primers in combination with RACE using muscle cDNA. The complete coding regions of AMPK α1 (1722 bp) and α2 (1674 bp) encoded 573 and 557 amino acids peptides, respectively. Multiple alignments, structural analysis and phylogenetic tree construction indicated that S. maximus AMPK α1 and α2 shared a high amino acid identity with other species, especially fish. AMPK α1 and α2 genes could be detected in all tested tissues, indicating that they are constitutively expressed. Salinity challenges significantly altered the gene expression levels of AMPK α1 and α2 mRNA in a salinity- and time-dependent manners in S. maximus gill tissues, suggesting that AMPK α1 and α2 played important roles in mediating the salinity stress in S. maximus. The expression levels of AMPK α1 and α2 mRNA were a positive correlation with gill Na+, K+-ATPase activities. These findings will aid our understanding of the molecular mechanism of juvenile turbot in response to environmental salinity changes.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteínas de Peixes/genética , Linguados/genética , Salinidade , Estresse Fisiológico/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar/genética , Proteínas de Peixes/metabolismo , Linguados/metabolismo , Expressão Gênica , Brânquias/enzimologia , Filogenia , Isoformas de Proteínas/genética , RNA Mensageiro/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
OBJECTIVE: To investigate the clinical effect of anterior cervical discectomy and fusion (ACDF) in the treatment of cervical spondylosis of vertebral artery type(CSA). METHODS: The clinical data of 42 patients with CSA from January 2020 to January 2022 were retrospectively analyzed. There were 25 males and 17 females, aged from 30 to 74 years old with an average of (53.9±11.0) years old. There were 18 cases with single-segment lesions, 17 cases with two-segment lesions, and 7 cases with three-segment lesions. The American Academy of Otolaryngology-Head and Neck Surgery's Hearing and Balance Committee score (CHE), the Neck Disability Index (NDI) and the cervical curvature Cobb angle were recorded before surgery and after surgery at 6 months. RESULTS: All 42 ACDF patients were followed up for 6 to 30 months with an average of (14.0±5.2) months. The operative time ranged from 95 to 220 min with an average of (160.38±36.77) min, the intraoperative blood loss ranged from 30 to 85 ml with an average of (53.60±18.98) ml. Tow patients had mild postoperative dysphagia, which improved with symptomatic treatment such as nebulized inhalation. CHE score decreased from (4.05±0.96) preoperatively to (2.40±0.70) at 6 months postoperatively (t=12.97, P<0.05). The number of improved vertigo at 6 months postoperatively was 38, with an improvement rate of 90.5%. NDI score was reduced from (34.43±8.04) preoperatively to (20.76±3.91) at 6 months postoperatively (t=11.83, P<0.05). The cervical curvature Cobb angle improved from (8.04±6.70)° preoperatively to (12.42±5.23)° at 6 months postoperatively (t=-15.96, P<0.05). CONCLUSION: The ACDF procedure has outstanding clinical efficacy in treating CSA. The operation can rapidly relieve patients' episodic vertigo symptoms by relieving bony compression and reconstructing cervical curvature. However, it is necessary to strictly grasp the indications for surgery and clarify the causes of vertigo in patients, and ACDF surgery is recommended for CSA patients for whom conservative treatment is ineffective.
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Vértebras Cervicais , Discotomia , Fusão Vertebral , Espondilose , Artéria Vertebral , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Discotomia/métodos , Fusão Vertebral/métodos , Espondilose/cirurgia , Idoso , Adulto , Vértebras Cervicais/cirurgia , Artéria Vertebral/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Microbial fuel cells (MFCs) are a promising technology for obtaining energy in wastewater. Effective extracellular electron transfer is one of the key factors for its practical application. In this work, carbon dots (CDs) enriched with oxygen-containing groups on the surface were synthesized as an efficient anode modifier using a simple hydrothermal method and common reactants. The experimental findings indicated that anodes modified with CDs exhibited increased electrical conductivity and greater hydrophilicity. These modifications facilitated increased microorganism loading and contributed to enhancing electrochemical processes within the anode biofilm. The CD-modified MFCs exhibited higher maximum power density (661.1 ± 42.6 mW·m-2) and open-circuit voltage (534.50 ± 6.4 mV), which were significantly better than those of the blank group MFCs (484.1 ± 14.1 mW·m-2 and 447.50 ± 12.1 mV). The use of simple carbon materials to improve the microbial loading on the MFCs anode and the electron transfer between the microbial-electrode may provide a new idea for the design of efficient MFCs.
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Huntington's disease is caused by expression of a mutant form of Huntingtin protein containing an expanded polyglutamine repeat. One possible treatment for Huntington's disease may be to reduce expression of mutant Huntingtin in the brain via RNA interference. Unless the therapeutic molecule is designed to be allele-specific, both wild-type and mutant protein will be suppressed by an RNA interference treatment. A key question is whether suppression of wild-type as well as mutant Huntingtin in targeted brain regions can be tolerated and result in a net benefit to patients with Huntington's disease. Whether Huntingtin performs essential functions in the adult brain is unclear. Here, we tested the hypothesis that the adult primate brain can tolerate moderately reduced levels of wild-type Huntingtin protein for an extended period of time. A serotype 2 adeno-associated viral vector encoding for a short hairpin RNA targeting rhesus huntingtin messenger RNA (active vector) was bilaterally injected into the striatum of four adult rhesus monkeys. Four additional animals received a comparable vector encoding a scrambled control short hairpin RNA (control vector). General health and motor behaviour were monitored for 6 months. Upon termination, brain tissues were sampled and assessed blindly for (i) huntingtin messenger RNA knockdown; (ii) Huntingtin protein expression; and (iii) neuropathological changes. Reduction in wild-type huntingtin messenger RNA levels averaging â¼30% was measured in the striatum of active vector recipients 6 months post-injection. A widespread reduction in Huntingtin protein levels was also observed by immunohistochemistry in these animals, with an average protein reduction of â¼45% relative to controls measured by western blot analysis in the putamen of active vector recipients. As with control vector recipients, no adverse effects were observed behaviourally, and no neurodegeneration was found on histological examination of active vector recipients. Our results suggest that long-term partial suppression of wild-type Huntingtin may be safe, and thus if a comparable level of suppression of mutant Huntingtin is beneficial, then partial suppression of both wild-type and mutant Huntingtin may result in a net benefit in patients with heterozygous Huntington's disease.
Assuntos
Doença de Huntington/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Interferência de RNA/fisiologia , Análise de Variância , Animais , Proteínas de Arabidopsis/metabolismo , Peso Corporal/genética , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Transformada , Colágeno/genética , Colágeno/metabolismo , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Ingestão de Alimentos/genética , Feminino , Regulação da Expressão Gênica/genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Transferases Intramoleculares/metabolismo , Macaca mulatta , Imageamento por Ressonância Magnética , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Desempenho Psicomotor/fisiologia , RNA Interferente Pequeno/administração & dosagem , TransfecçãoRESUMO
AIMS: To investigate the expression of placental growth factor (PIGF) in alkali burn-induced murine corneal neovascularization (NV); to evaluate the effects of KH902, a vascular endothelial growth factor receptor decoy, on prevention and regression of new vessels growths in the cornea; and to determine the influence of KH902 on the levels of vascular endothelial growth factor (VEGF) and PIGF in alkali burn-induced corneal NV. METHODS: Mouse corneal NV was induced by alkali burn. The expression of PIGF was detected by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR). To evaluate the effects of KH902, corneal NV was observed and photographed every 3 days for a total of 28 days after the alkali burn. The percentage of NV area was measured and compared with that of the control group. The VEGF and PIGF levels in the cornea were evaluated by enzyme linked immunosorbent assay (ELISA). RESULTS: PIGF was expressed during the alkali burn-induced corneal neovascularization. On day 3 (D3), day 6 (D6) and day 9 (D9) after chemical cauterization, the length of the longest new vessel and the neovascularization areas in the KH902-treated groups were significantly smaller than those of the PBS-treated group (p < 0.05). The areas of established corneal NV of the KH902-treated groups regressed with time, but the control groups showed no natural regression. The VEGF and PIGF levels of the cornea in the treated groups were significantly decreased compared to those of the control group (p < 0.05). CONCLUSIONS: PIGF may be involved in alkali burn-induced corneal NV. KH902 significantly inhibited new vessel growth and promoted the regression of established vessels in a mouse model of corneal NV, and it also reduced the levels of VEGF and PIGF in the cornea.
Assuntos
Queimaduras Químicas/complicações , Neovascularização da Córnea/tratamento farmacológico , Queimaduras Oculares/induzido quimicamente , Proteínas da Gravidez/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Queimaduras Químicas/metabolismo , Córnea/efeitos dos fármacos , Neovascularização da Córnea/induzido quimicamente , Neovascularização da Córnea/metabolismo , Modelos Animais de Doenças , Queimaduras Oculares/complicações , Queimaduras Oculares/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Placentário , Proteínas Recombinantes de Fusão/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Background: The pain-fatigue-sleep disturbance symptom cluster is commonly experienced by breast cancer patients, and a variety of nonpharmacological interventions are used to treat this symptom cluster. Objective: To compare the efficacy of nonpharmacological interventions in improving the symptoms of the pain-fatigue-sleep disturbance symptom cluster in breast cancer patients. Methods: A comprehensive literature search was conducted in the PubMed, EMBASE, Cochrane Library, CINAHL, CNKI, and Wanfang databases to identify randomized controlled studies from database inception to May 2022. Two reviewers independently performed data retrieval and risk of bias assessments. The consistency model was used to conduct network meta-analyses (NMA) based on the frequentist framework to assess the interventions, which were ranked by the surface under the cumulative ranking curve (SUCRA). Finally, the CINeMA application was used to evaluate the results of the NMA and the evidence of quality. The results Twenty-three eligible studies assessing 14 interventions were included. According to SUCRA values, among the management effects of the three symptoms, the effect of progressive muscle relaxation (PMR) ranked first, followed by mindfulness-based stress reduction (MBSR). The overall evidence quality of our study ranges from very low to moderate. Conclusion: PMR and MBSR were effective interventions for the pain-fatigue-sleep disturbance symptom cluster in breast cancer patients. Clinical recommendations prioritize PMR for symptom management, followed by MBSR. However, this should be interpreted cautiously, as the confidence in the evidence was not high.
RESUMO
Blumeatin, reported herein, bearing two hydroxyl groups at C3' and C5' of ring B, is isolated from the traditional Chinese medicine Blumea balsamifera. But the isolation procedure of blumeatin from plants has limitations of prolonged duration and high cost. A procedure featuring Lewis acid-catalyzed ring closure and chiral resolution via Schiff base intermediates is provided here to prepare optically pure blumeatin and its R-isomer efficiently. Furthermore, the structure revision of putative blumeatin based on a logically synthetic procedure and NMR spectroscopic analysis was conducted. The 1D and 2D NMR data analysis unambiguously confirmed our proposal that the reported blumeatin structure has been misassigned as it corresponds to sterubin, which contains two hydroxyl groups at C3' and C4' of ring B. Finally, the results of the ear-swelling test exhibited that synthetic (±)-blumeatin and (±)-sterubin had moderate anti-inflammatory activity which was less than that of (-)-sterubin.
RESUMO
BACKGROUND: A recent epidemic of melamine contamination of baby formula in China has been associated with the development of urinary tract stones, though the clinical manifestations and predisposing factors are incompletely delineated. METHODS: We administered a questionnaire to the parents of children 36 months of age or younger who were being screened for a history of exposure to melamine and symptoms of, and possible predisposing factors for, urinary tract stones. In addition, we performed urinalysis, renal-function and liver-function tests, urinary tests for biochemical markers and the calcium:creatinine ratio, and ultrasonography. Powdered-milk infant formulas were classified as having a high melamine content (>500 ppm), a moderate melamine content (<150 ppm), or no melamine (0 ppm); no formulas contained between 150 and 500 ppm of melamine. RESULTS: Contaminated formula was ingested by 421 of 589 children. Fifty had urinary stones, including 8 who had not received melamine-contaminated formula; 112 were suspected to have stones; and 427 had no stones. Among children with stones, 5.9% had hematuria and 2.9% had leukocyturia, percentages that did not differ significantly from those among children who were suspected to have stones or those who did not have stones. Serum creatinine, urea nitrogen, and alanine aminotransferase levels were normal in the 22 children with stones who were tested. Four of the 41 children (9.8%) who had stones and in whom urinary markers of glomerular function were measured had evidence of abnormalities; none had tubular dysfunction. Children exposed to high-melamine formula were 7.0 times as likely to have stones as those exposed to no-melamine formula. Preterm infants were 4.5 times as likely to have stones as term infants. CONCLUSIONS: Prematurity and exposure to melamine-contaminated formula were associated with urinary stones. Affected children lacked typical signs and symptoms of urolithiasis.
Assuntos
Contaminação de Alimentos , Fórmulas Infantis/química , Triazinas/efeitos adversos , Urolitíase/etiologia , Distribuição de Qui-Quadrado , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Modelos Logísticos , Masculino , Fatores de Risco , Inquéritos e Questionários , Triazinas/análise , Ultrassonografia , Cálculos Urinários/diagnóstico por imagem , Cálculos Urinários/epidemiologia , Cálculos Urinários/etiologia , Sistema Urinário/diagnóstico por imagem , Urolitíase/diagnóstico por imagemRESUMO
Pathological retinal neovascularization and choroidal neovascularization are major causes of vision loss in a variety of clinical conditions, such as retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy. Pigment epithelial-derived factor (PEDF) has been found to be the most potent natural, endogenous inhibitor of neovascularization, but its application is restricted because of its instability and short half-life. Polyethylene glycol (PEG) has been used as a drug carrier to slow clearance rate for decades. The present study investigated PEGylated-PEDF for the first time and evaluated its long-term effects on preventing angiogenesis in vitro and in vivo. PEG showed lower cytotoxicity to human umbilical vein endothelial cells (HUVECs). In vitro, PEGylated-PEDF inhibited HUVEC proliferation, migration, tube formation, and vascular endothelium growth factor secretion and induced HUVEC apoptosis in a dose-dependent manner, and it showed a statistically significant difference compared with the PEDF treatment group. In vivo, PEGylated-PEDF had a long-lasting effect in both plasma and retinal concentrations. In an oxygen-induced retinopathy model, one intravitreous injection of PEGylated-PEDF after mouse pups were moved into room air resulted in a significant difference in the inhibition of retinal neovascularization, which decreased the nonperfusion area, compared with the PEDF-treated group. Our present study demonstrated for the first time the long-term inhibitory effects of PEGylated-PEDF on the prevention of neovascularization in vitro and in vivo. These data suggest that PEGylated-PEDF could offer an innovative therapeutic strategy for preventing retinal neovascularization.