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Predation risk may affect the foraging behavior of birds. However, there has been little research on the ability of domestic birds to perceive predation risk and thus adjust their feeding behavior. In this study, we tested whether domestic budgerigars (Melopsittacus undulatus) perceived predation risk after the presentation of specimens and sounds of sparrowhawks (Accipiter nisus), domestic cats (Felis catus), and humans, and whether this in turn influenced their feeding behavior. When exposed to visual or acoustic stimuli, budgerigars showed significantly longer latency to feed under sparrowhawk, domestic cat, and human treatments than with controls. Budgerigars responded more strongly to acoustic stimuli than visual stimuli, and they showed the longest latency to feed and the least number of feeding times in response to sparrowhawk calls. Moreover, budgerigars showed shorter latency to feed and greater numbers of feeding times in response to human voices than to sparrowhawk or domestic cat calls. Our results suggest that domestic budgerigars may identify predation risk through visual or acoustic signals and adjust their feeding behavior accordingly.
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Percepção Auditiva , Melopsittacus , Humanos , Animais , Gatos , Percepção Auditiva/fisiologia , Melopsittacus/fisiologia , Comportamento Predatório , Acústica , SomRESUMO
The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.
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Antibacterianos , DNA Girase , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , DNA Girase/metabolismo , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/síntese química , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Relação Dose-Resposta a Droga , Camundongos , Células Hep G2 , Simulação de Acoplamento Molecular , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/químicaRESUMO
Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.
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Degeneração Macular , Camundongos , Animais , Humanos , Camundongos Endogâmicos ICR , Células Endoteliais da Veia Umbilical Humana , Degeneração Macular/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio VascularRESUMO
Alzheimer's disease (AD), a progressive neurodegenerative disorder, has garnered increased attention due to its substantial economic burden and the escalating global aging phenomenon. Amyloid-ß deposition is a key pathogenic marker observed in the brains of Alzheimer's sufferers. Based on real-time, safe, low-cost, and commonly used, near-infrared fluorescence (NIRF) imaging technology have become an essential technique for the detection of AD in recent years. In this work, NIRF probes with hemicyanine structure were designed, synthesized and evaluated for imaging Aß aggregates in the brain. We use the hemicyanine structure as the parent nucleus to enhance the probe's optical properties. The introduction of PEG chain is to improve the probe's brain dynamice properties, and the alkyl chain on the N atom is to enhance the fluorescence intensity of the probe after binding to the Aß aggregates as much as possible. Among these probes, Z2, Z3, Z6, X3, X6 and T1 showed excellent optical properties and high affinity to Aß aggregates (Kd = 24.31 â¼ 59.60 nM). In vitro brain section staining and in vivo NIRF imaging demonstrated that X6 exhibited superior discrimination between Tg mice and WT mice, and X6 has the best brain clearance rate. As a result, X6 was identified as the optimal probe. Furthermore, the docking theory calculation results aided in describing X6's binding behavior with Aß aggregates. As a high-affinity, high-selectivity, safe and effective probe of targeting Aß aggregates, X6 is a promising NIRF probe for in vivo detection of Aß aggregates in the AD brain.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Carbocianinas , Desenho de Fármacos , Corantes Fluorescentes , Imagem Óptica , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/análise , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Animais , Carbocianinas/química , Carbocianinas/síntese química , Camundongos , Estrutura Molecular , Humanos , Agregados Proteicos , Relação Estrutura-Atividade , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Relação Dose-Resposta a DrogaRESUMO
Land use changes driven by human activities significantly impact biodiversity in plateau regions. However, current research is largely confined to identifying correlations between various factors and both habitat quality and degradation, overlooking the nonlinear relationships between them. To address this gap, we applied the PLUS-INVEST model to investigate the spatial effects of land-use changes on habitat quality and degradation patterns across the Tibetan Plateau during the 21st century. By employing a geographic detector, we determined the contribution rates of disturbance factors to habitat quality and degradation, and established constraint lines and threshold ranges between these factors. The findings reveal that: (1) The PLUS model demonstrates an exceptional performance in land-use simulation, with an overall accuracy of 0.8465. (2) The high-quality habitat area exhibits a declining trend, while the habitat degradation index steadily rises from 2000 to 2100, indicating a significant loss of biodiversity within the region. Habitat quality displays a spatial distribution pattern characterized by higher values in the south and lower values in the north, with areas in proximity to road threat sources experiencing more pronounced habitat degradation. (3) NDVI emerges as the most influential factor in promoting habitat quality, while the interaction of NDVI_Temperature exerts the greatest influence on spatial heterogeneity. The distance to resident emerges as the primary disturbance factor contributing to habitat degradation, with the interaction strength of GI_Resident being the most significant contributor. (4) Threshold intervals for ANPP, NDVI, precipitation, temperature, and distance to resident of optimal habitat quality and most severe degradation. This provides a novel scientific approach for designating areas for targeted conservation and intensive management restoration.
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The establishment of bipolar spindles during meiotic divisions ensures faithful chromosome segregation to prevent gamete aneuploidy. We analyzed centriole duplication, as well as centrosome maturation and separation during meiosis I and II using mouse spermatocytes. The first round of centriole duplication occurs during early prophase I, and then, centrosomes mature and begin to separate by the end of prophase I to prime formation of bipolar metaphase I spindles. The second round of centriole duplication occurs at late anaphase I, and subsequently, centrosome separation coordinates bipolar segregation of sister chromatids during meiosis II. Using a germ cell-specific conditional knockout strategy, we show that Polo-like kinase 1 and Aurora A kinase are required for centrosome maturation and separation prior to metaphase I, leading to the formation of bipolar metaphase I spindles. Furthermore, we show that PLK1 is required to block the second round of centriole duplication and maturation until anaphase I. Our findings emphasize the importance of maintaining strict spatiotemporal control of cell cycle kinases during meiosis to ensure proficient centrosome biogenesis and, thus, accurate chromosome segregation during spermatogenesis.
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Aurora Quinase A , Espermatócitos , Animais , Aurora Quinase A/genética , Proteínas de Ciclo Celular/genética , Centrossomo , Masculino , Meiose , Camundongos , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Fuso Acromático , Quinase 1 Polo-LikeRESUMO
A novel series of N-methyl-propargylamine derivates were designed, synthesized, and evaluated as isoform-selective monoamine oxidases (MAO) inhibitors for the treatment of nervous system diseases. The in vitro studies showed some of the compounds exhibited considerable MAO-A selective inhibitory activity (IC50 of 14.86-17.16 nM), while some of the others exhibited great MAO-B selective inhibitory activity (IC50 of 4.37-17.00 nM). Further studies revealed that compounds A2 ï¼IC50 against MAO-A: 17.16 ± 1.17 nMï¼ and A5 (IC50 against MAO-B: 17.00 ± 1.10 nM) had significant abilities to protect PC12 cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The parallel artificial membrane permeability assay showed A2 and A5 would be potent to cross the blood-brain barrier. The results indicated that A2 showed potential use in the therapy of MAO-A related diseases, such as depression and anxiety; while A5 exhibited promising ability in the treatment of MAO-B related diseases, such as Alzheimer's disease and Parkinson's disease.
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Doença de Alzheimer , Peróxido de Hidrogênio , Ratos , Animais , Relação Estrutura-Atividade , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismoRESUMO
Long-range surface plasmon resonance (LRSPR) has demonstrated excellent performance in sensing and detection, due to its higher accuracy and sensitivity compared with conventional surface plasmon resonance (cSPR). In this work, we establish an LRSPR biosensor which employs PDA/Ti3C2-MXene/PDA-gold film as a sensing substrate and gold nanoparticles (AuNPs) as enhancers. Ti3C2-MXene is an emerging two-dimensional (2D) layered material which is used extensively in immunoassay and biosensing. The sensing substrate comprises two polydopamine (PDA) films between which is sandwiched a Ti3C2-MXene film based on a gold film, which provides a large surface area and abundant binding sites to rabbit anti-human IgG (Ab1). Sandwich amplification is adopted to enhance the sensitivity of the LRSPR biosensor, and AuNPs/staphylococcal protein A (SPA)/mouse anti-human IgG (Ab2) composites are introduced into the flow cell as enhancers after the immune binding of human IgG to Ab1. The antigen (human IgG) detection range is 0.075 µg mL-1 to 40 µg mL-1, and the limit of detection is almost 20 times lower than that for cSPR biosensors. This novel LRSPR biosensor demonstrates excellent performance in immune sensing over a broad detection range and a low limit of detection. Subsequent modification of the LRSPR sensing platform could be made for extensive application in various biological detection fields.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Animais , Técnicas Biossensoriais/métodos , Ouro/química , Humanos , Imunoglobulina G , Limite de Detecção , Nanopartículas Metálicas/química , Camundongos , Coelhos , Ressonância de Plasmônio de Superfície/métodos , Titânio/químicaRESUMO
High energy density is the major demand for next-generation rechargeable batteries, while the intrinsic low alkali metal adsorption of traditional carbon-based electrode remains the main challenge. Here, the mechanochemical route is proposed to prepare nitrogen doped γ-graphyne (NGY) and its high capacity is demonstrated in lithium (LIBs)/sodium (SIBs) ion batteries. The sample delivers large reversible Li (1037 mAh g-1 ) and Na (570.4 mAh g-1 ) storage capacities at 100 mA g-1 and presents excellent rate capabilities (526 mAh g-1 for LIBs and 180.2 mAh g-1 for SIBs) at 5 A g-1 . The superior Li/Na storage mechanisms of NGY are revealed by its 2D morphology evolution, quantitative kinetics, and theoretical calculations. The effects on the diffusion barriers (Eb ) and adsorption energies (Ead ) of Li/Na atoms in NGY are also studied and imine-N is demonstrated to be the ideal doping format to enhance the Li/Na storage performance. Besides, the Li/Na adsorption routes in NGY are optimized according to the experimental and the first-principles calculation results. This work provides a facile way to fabricate high capacity electrodes in LIBs/SIBs, which is also instructive for the design of other heteroatomic doped electrodes.
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A versatile and robust chiral discrimination strategy for small aromatic compounds is of significant importance in multidisciplinary fields. However, most current methods lack either the sufficient sensitivity for recognizing the chirality of the target molecules or their molecular specificity information. We have developed a versatile and chiral-label-free surface-enhanced Raman scattering (SERS)-based chiral discrimination sensing system for small aromatic molecules, where the molecular structural specificity and enantioselectivity can be given synchronously in a single SERS spectrum. More than 10 types of chiral aromatic molecules were successfully identified by using this system. This work has enormous potential for recognizing chiral products effectively in sophisticated systems, especially in the fields of chiral synthesis and chiral catalysis.
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BACKGROUND: Bartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss, metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure. BS type III, often known as classic BS (CBS), is caused by loss-of-function mutations in CLCNKB (chloride voltage-gated channel Kb) encoding basolateral ClC-Kb. CASE PRESENTATION: We reported a 15-year-old CBS patient with a compound heterozygous mutation of CLCNKB gene. She first presented with vomiting, hypokalemic metabolic alkalosis at the age of 4 months, and was clinically diagnosed as CBS. Indomethacin, spironolactone and oral potassium were started from then. During follow-up, the serum electrolyte levels were generally normal, but the patient showed failure to thrive and growth hormone (GH) deficiency was diagnosed. The recombinant human GH therapy was performed, and the growth velocity was improved. When she was 14, severe proteinuria and chronic kidney disease (CKD) were developed. Renal biopsy showed focal segmental glomerulosclerosis (FSGS) with juxtaglomerular apparatus cell hyperplasia, and genetic testing revealed a point deletion of c.1696delG (p. Glu566fs) and a fragment deletion of exon 2-3 deletions in CLCNKB gene. Apart from the CBS, ostium secundum atrial septal defect (ASD) was diagnosed by echocardiography. CONCLUSIONS: This is the first report of this compound heterozygous of CLCNKB gene in BS Children. Our findings contribute to a growing list of CLCNKB mutations associated with CBS. Some recessive mutations can induce CBS in combination with other mutations.
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Povo Asiático/genética , Síndrome de Bartter/genética , Canais de Cloreto/genética , Predisposição Genética para Doença/genética , Mutação , Adolescente , Síndrome de Bartter/patologia , Nanismo Hipofisário/genética , Feminino , Estudos de Associação Genética , Comunicação Interatrial , Heterozigoto , Humanos , Sistema Justaglomerular , Linhagem , Insuficiência Renal CrônicaRESUMO
AIM: We aimed at investigating the effects of age on the predictive performances of noninvasive fibrosis scores for significant fibrosis in patients with chronic hepatitis B (CHB). METHODS: A total of 496 CHB patients who underwent liver biopsy were stratified into four age groups: ≤30, 31 to 40, 41 to 50, and ≥51 years. Receiver operating characteristic curves were used to evaluate the diagnostic performance of aspartate aminotransferase to platelet ratio index (APRI), fibrosis score-4 (Fib-4) and γ-glutamyl transpeptidase to platelet ratio (GPR) in different age groups. RESULTS: The extent of fibrosis significantly increased with age, and the percentage of significant fibrosis (≥F2) was 21.3%, 29.0%, 38.5%, and 46.1%, respectively. All three scores displayed a moderate accuracy to diagnose significant fibrosis in overall patients. However, for patients with age ≤30 years, APRI, Fib-4, and GPR performed poorly with the AUROC of 0.567, 0.627 and 0.596, respectively. Furthermore, using the established cut-off values-1.45 for Fib-4, the sensitivity for significant fibrosis increased with age, from 14.8%, 38.1%, 74.5% to 97.87% in above age groups, respectively. To improve the diagnostic accuracy for significant fibrosis, the proposed low and high cut-off points for Fib-4 were 0.41 and 1.15 in ≤30 years, 0.8 and 1.59 in 31 to 40 years, 1.17 and 1.94 in 41 to 50 years, 1.76 and 3.10 in ≥ 51 years, respectively. CONCLUSIONS: Age may influence the diagnostic thresholds and performance of APRI, Fib-4, and GPR for significant fibrosis in patients with CHB. In particular, these scores performed poorly for identifying significant fibrosis in younger patients (≤30 years).
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Hepatite B Crônica/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Fatores Etários , Biópsia , Feminino , Hepatite B Crônica/patologia , Humanos , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
Pain is one of the problems that seriously affect people's quality of life for thousands of years. The causes of pain are complex and varied,and long-term pain can also lead to depression. It has become a research hotspot to develop analgesic preparations with significant drug effects and small side effects. Recent studies have shown that certain alkaloid monomers have analgesic targets such as γ-aminobutyric acid,cannabinoids,and capsaicin. If their preparation is applied to the analgesic field,they can make up for the defects such as strong addiction and side effects of traditional opioid and non-steroidal analgesic drugs,but there is no relevant literature to summarize the research results in this field. This article first introduces the mechanism of pain production and the target of analgesia. Based on this,the application status of alkaloid monomer analgesic preparations approved by China Food and Drug Administration( CFDA)( number varieties,type of dosage form,drug description,analgesic mechanism and advantages) was analyzed,and the research dynamics of alkaloid monomer analgesic preparations( new formulation and new technology) were reviewed. Finally,some problems in this field were pointed out,such as imperfect medication information,inadequate transformation of research results,and too few kinds of analgesic components in developed alkaloids. The development direction was also pointed out for the above problems,with a view to provide reference for further development and in-depth research.
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Alcaloides/farmacologia , Analgésicos/farmacologia , Dor/tratamento farmacológico , Analgesia , China , Humanos , Qualidade de VidaRESUMO
Reduced radiosensitivity of lung cancer cells represents a pivotal obstacle in clinical oncology. The hypoxia-inducible factor (HIF)-1α plays a crucial role in radiosensitivity, but the detailed mechanisms remain elusive. A relationship has been suggested to exist between hypoxia and autophagy recently. In the current study, we studied the effect of hypoxia-induced autophagy on radioresistance in lung cancer cell lines. A549 and H1299 cells were cultured under normoxia or hypoxia, followed by irradiation at dosage ranging from 0 to 8 Gy. Clonogenic assay was performed to calculate surviving fraction. EGFP-LC3 plasmid was stably transfected into cells to monitor autophagic processes. Western blotting was used to evaluate the protein expression levels of HIF-1α, c-Jun, phosphorylated c-Jun, Beclin 1, LC3 and p62. The mRNA levels of Beclin 1 were detected by qRT-PCR. We found that under hypoxia, both A549 and H1299 cells were radio-resistant compared with normoxia. Hypoxia-induced elevated HIF-1α protein expression preferentially triggered autophagy, accompanied by LC3 induction, EGFP-LC3 puncta and p62 degradation. In the meantime, HIF-1α increased downstream c-Jun phosphorylation, which in turn upregulated Beclin 1 mRNA and protein expression. The upregulation of Beclin 1 expression, instead of HIF-1α, could be blocked by SP600125 (a specific inhibitor of c-Jun NH2-terminal kinase), followed by suppression of autophagy. Under hypoxia, combined treatment of irradiation and chloroquine (a potent autophagy inhibitor) significantly decreased the survival potential of lung cancer cells in vitro and in vivo. In conclusion, hypoxia-induced autophagy through evaluating Beclin1 expression may be considered as a target to reverse the radioresistance in cancer cells.
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Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína Beclina-1 , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Immunoblotting , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Camundongos Nus , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação , Tolerância a Radiação/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , Carga Tumoral/genéticaRESUMO
Molecular breeding methods, such as marker-assisted selection and genomic selection, require high-throughput and cost-effective methods for isolating genomic DNA from plants, specifically from crop tissue or seed with high polysaccharides, lipids, and proteins. A quick and inexpensive high-throughput method for isolating genomic DNA from seed and leaf tissue from multiple crops was tested with a DNA isolation method that combines CTAB extraction buffer and lab-made SA-coated magnetic nanoparticles. This method is capable of isolating quality genomic DNA from leaf tissue and seeds in less than 2 hours with fewer steps than a standard CTAB extraction method. The yield of the genomic DNA was 582-729 ng per 5 leaf discs or 216-1869 ng per seed in soybean, 2.92-62.6 ng per 5 leaf discs or 78.9-219 ng per seed in wheat, and 30.9-35.4 ng per 5 leaf discs in maize. The isolated DNA was tested with multiple molecular breeding methods and was found to be of sufficient quality and quantity for PCR and targeted genotyping by sequencing methods such as molecular inversion probes (MIPs). The combination of SA-coated magnetic nanoparticles and CTAB extraction buffer is a fast, simple, and environmentally friendly, high-throughput method for both leaf tissues and seed(s) DNA preparation at low cost per sample. The DNA obtained from this method can be deployed in applied breeding programs for marker-assisted selection or genomic selection.
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Nanopartículas de Magnetita , Cetrimônio , Melhoramento Vegetal , Sementes/genética , Inversão Cromossômica , Sondas MolecularesRESUMO
In this study, a series of carbamate derivatives incorporating multifunctional carrier scaffolds were designed, synthesized, and evaluated as potential therapeutic agents for Alzheimer's disease (AD). We used tacrine to modify the aliphatic substituent, and employed rivastigmine, indole and sibiriline fragments as carrier scaffolds. The majority of compounds exhibited good inhibitory activity for cholinesterase. Notably, compound C7 with sibiriline fragment exhibited potent inhibitory activities against human acetylcholinesterase (hAChE, IC50 = 30.35 ± 2.07 nM) and human butyrylcholinesterase (hBuChE, IC50 = 48.03 ± 6.41 nM) with minimal neurotoxicity. Further investigations have demonstrated that C7 exhibited a remarkable capacity to safeguard PC12 cells against H2O2-induced apoptosis and effectively suppressed the production of reactive oxygen species (ROS). Moreover, in an inflammation model of BV2 cells induced by lipopolysaccharide (LPS), C7 effectively attenuated the levels of pro-inflammatory cytokines. After 12 h of dialysis, C7 continued to exhibit an inhibitory effect on cholinesterase activity. An acute toxicity test in vivo demonstrated that C7 exhibited a superior safety profile and no hepatotoxicity compared to the parent nucleus tacrine. In the scopolamine-induced AD mouse model, C7 (20 mg/kg) significantly reduced cholinesterase activity in the brain of the mice. C7 was tested in a pharmacological AD mouse model induced by Aß1-42 and attenuated memory deficits at doses as low as 5 mg/kg. The pseudo-irreversible cholinesterase inhibitory properties and multifunctional therapeutic attributes of C7 render it a promising candidate for further investigation in the treatment of AD.
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Doença de Alzheimer , Inibidores da Colinesterase , Ratos , Camundongos , Humanos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/induzido quimicamente , Butirilcolinesterase/metabolismo , Tacrina/farmacologia , Tacrina/uso terapêutico , Acetilcolinesterase/metabolismo , Carbamatos/farmacologia , Peróxido de Hidrogênio/farmacologia , Peptídeos beta-Amiloides , Barreira Hematoencefálica/metabolismo , Desenho de Fármacos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Lichenoid amyloidosis (LA) is a subtype of primary cutaneous amyloidosis characterized by persistent multiple groups of hyperkeratotic papules, usually on the lower leg, back, forearm, or thigh. LA may be associated with several skin diseases, including atopic dermatitis (AD). The treatment of LA is considered to be difficult. However, as there is some overlap in the etiopathogenesis of LA and AD, AD treatment may also be effective for LA. CASE SUMMARY: Case 1: A 70-year-old man was diagnosed with severe AD with LA based on large dark erythema and papules on the trunk and buttocks and dense hemispherical millet-shaped papules with pruritus on the extensor side of the lower limbs. He had a long history of the disease (8 years), with repeated and polymorphic skin lesions. Given the poor efficacy of traditional treatments, this patient was recommended to receive dupilumab treatment. At the initial stage, 300 mg was injected subcutaneously every 2 wk. After 28 wk, the drug interval was extended to 1 mo due to the pandemic. Follow-up observations revealed that the patient reached an Eczema Area Severity Index of 90 (skin lesions improved by 90% compared with the baseline) by the end of the study. Moreover, Investigator's Global Assessment score was 1, and scoring atopic dermatitis index and numeric rating scale improved by 97.7% and 87.5% compared with the baseline, respectively, with LA skin lesions having largely subsided. Case 2: A 30-year-old woman was diagnosed with severe AD with LA, due to dense and substantial papules on the dorsal hands similar to changes in cutaneous amyloidosis, and erythema and papules scattered on limbs and trunk with pruritus, present for 25 years. After 16 wk of dupilumab treatment, she stopped, and skin lesions completely subsided, without recurrence since the last follow-up. CONCLUSION: Dupilumab shows rational efficacy and safety in the treatment of severe AD with LA, in addition to benefits in the quality of life of the patients.
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Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. The previous studies demonstrated that the endocannabinoid system played important roles in modulating several physiological functions such as sleep, olfaction, emotion, learning and memory, and reward behaviors. Mouse VD-hemopressin (α) [(m)VD-HPα], an 11-residue peptide derived from the α1 chain of hemoglobin, was recently presumed as a selective agonist of the CB1 receptor. The present study was undertaken to investigate the effects of (m)VD-HPα on the sleep-wake cycle and power spectrum of cortical EEG in freely moving rats and the potential neurons in the brain activated by (m)VD-HPα. The results showed that 20.1 nmol of (m)VD-HPα i.c.v. administration increased non-rapid eye movement (NREM) sleep in the first 2 h section accompanied by an increase in EEG delta (0.5-4 Hz) activity. The (m)VD-HPα-induced NREM sleep enhancement was due to extended episode duration instead of the episode number. In addition, the effect of (m)VD-HPα (20.1 nmol) on sleep-wake states was significantly attenuated by an antagonist of the CB1 receptor, AM251 (20 nmol, i.c.v.) but not by the CB2 receptor antagonist, AM630 (20 nmol, i.c.v.). In comparison with vehicle, (m)VD-HPα increased Fos-immunoreactive (-ir) neurons in the ventrolateral preoptic nucleus (VLPO), but reduced Fos-ir neurons in the lateral hypothalamus (LH), tuberomammillary nucleus (TMN), and locus coeruleus (LC). These findings suggest that (m)VD-HPα promotes NREM sleep via the CB1 cannabinoid receptor to probably activate VLPO GABAergic neurons, but inactivates the LH orexinergic, LC noradrenergic, and TMN histaminergic neurons.
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Background: The resistance mechanisms to osimertinib encompass on-target molecular alterations, such as the well-known epidermal growth factor receptor (EGFR) C797S resistance mutation, and off-target molecular alterations, such as the high-frequency MET amplification, but there's no further clear-cut therapeutic option to date for these individuals yet. Here we reported a lung adenocarcinoma (LUAD) patient who progressed on osimertinib benefited from multiline combination target-therapy and obtained a long-term progression-free survival (PFS). Case Description: A 70-year-old Chinese woman without a smoking history presented with stage IV advanced LUAD harboring EGFR 19del and then developed EGFR T790M mutation after 6-month treatment of gefitinib [a first-generation EGFR tyrosine kinase inhibitor (TKI)]. Osimertinib (a third-generation EGFR TKI) was immediately initiated, and the PFS was 11 months. After disease progression, next-generation sequencing (NGS) identified MET amplification, in addition to EGFR 19del. Combination therapy of osimertinib and cabozantinib (a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2)/capmatinib (a MET inhibitor) was administrated to the patient and the best overall response (OR) was stable disease (SD) with the PFS of 10 months. NGS detected the emergence of novel mutations EGFR S784Y and EGFR L799Q, together with EGFR C797S and all in cis with EGFR T790M, and retention of EGFR 19 del. The patient received pemetrexed (a chemotherapy drug) and bevacizumab (a VEGFR inhibitor) and achieved a partial response (PR). After 6 months of PFS, combination therapy of brigatinib (an inhibitor of ALK and EGFR) and cetuximab (an EGFR inhibitor) was initiated and the patient achieved a long-term PFS of 18 months and SD. Her overall survival (OS) was 51 months. Conclusions: This case highlights the importance of NGS on repeated biopsy which could offer better treatment options.