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Nucleic acids, including DNA and RNA, have been considered as powerful and functional biomaterials owing to their programmable structure, good biocompatibility, and ease of synthesis. However, traditional nucleic acid-based probes have always suffered from inherent limitations, including restricted cell internalization efficiency and structural instability. In recent years, DNA nanotechnology has shown great promise for the applications of bioimaging and drug delivery. The attractive superiorities of DNA nanostructures, such as precise geometries, spatial addressability, and improved biostability, have enabled them to be a novel category of nucleic acid delivery systems for biomedical applications. In this review, we introduce the development of DNA nanotechnology, and highlight recent advances of DNA nanostructure-based delivery systems for cellular imaging and therapeutic applications. Finally, we propose the challenges as well as opportunities for the future development of DNA nanotechnology in biomedical research.
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Nanoestruturas , Ácidos Nucleicos , Nanotecnologia/métodos , DNA/genética , DNA/química , Nanoestruturas/química , Sistemas de Liberação de MedicamentosRESUMO
Context: Helicobacter pylori (H. pylori) infection has become a global public-health problem, and people living in low-resource settings may be more likely to be infected because of unhealthy life habits, poor sanitary conditions, and overuse of antibiotics without a prescription. Objectives: The study intended to assess the susceptibility of H. pylori to nine antibiotics commonly prescribed for eradication of H. pylori infections among minority people in Yunnan province, China, to provide updated recommendations for H. pylori eradication therapy among adults. Design: The research team designed a cross-sectional observational study. Setting: The study took place in the First Affiliated Hospital of Kunming Medical University, Yunnan Province. Participants: Participants were 276 people in the Mosuo or Pumi minority population who had lived on the shores of Lugu Lake in Ninglang county, Yunnan province in China for generations. Outcome Measures: After completing a questionnaire, all participants underwent 13C-urea breath test, and those with a positive result participated in an antimicrobial-susceptibility test. For each H. pylori isolate, the research team tested the minimum inhibitory concentrations (MICs) of nine commonly used antibiotics: amoxicillin, azithromycin, levofloxacin, clarithromycin, metronidazole, tetracycline, rifampicin, gentamicin, and moxifloxacin. Results: The research team confirmed that 276 participants were resistant to at least one antibiotic. The resistances rates for moxifloxacin, metronidazole, and levofloxacin were the highest, while that for amoxicillin was the lowest, and no isolates were resistant to gentamicin. Double resistance (33.20%) had the highest proportion of all multiple-resistance patterns. Moreover, the metronidazole resistance rate was higher in females than in males and in nonsmokers than in smokers, and rifampicin resistance was higher in nondrinkers than in drinkers, suggesting that smoking and drinking might be protective against metronidazole and rifampicin resistance. Conclusions: Most of the Mosuo and Pumi people in Yunnan were resistant to antibiotics. Moxifloxacin, metronidazole, and levofloxacin should no longer be the main medicines for H. pylori, whereas amoxicillin and gentamicin should be recommended to be the first-line clinical therapy for H. pylori eradication regimens.
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Infecções por Helicobacter , Helicobacter pylori , Adulto , Masculino , Feminino , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Levofloxacino/farmacologia , Levofloxacino/uso terapêutico , Moxifloxacina/uso terapêutico , Rifampina/uso terapêutico , Estudos Transversais , População do Leste Asiático , Farmacorresistência Bacteriana , Farmacorresistência Bacteriana Múltipla , China/epidemiologia , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/epidemiologia , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , GentamicinasRESUMO
METHODS: 8-week-age male ApoE(-/-) mice were fed with the atherogenic diet together with or without tested compounds (rosuvastatin calcium, α-LNA-LMWCS, LMWCS and α-LNA) for 16 weeks. When the animals were killed, blood plasma was isolated to test the level of TC, LDL-C, TNF-α, IL-6 and CRP by biochemistry analysis and ELISA method. The whole aorta and aortic root sections were also collected to study atherogenesis level and reveal the possible mechanism by histological examination, real-time PCR and Western blot analysis. RESULTS: The level of TC, LDL-C, TNF-α, IL-6 and CRP in plasma in H-LNA-LMWCS group were significantly lower than those of the control group (rosuvastatin calcium). Plaques in H-LNA-LMWCS group showed higher content of smooth muscle cells, lower content of lipid and macrophages, and lower mRNA levels of TNF-α, IL-6, CRP, MCP-1, VCAM-1 and ICAM-1 than those in the control group. In addition, α-LNA-LMWCS could reduce the nuclear translocation of NF-κB, inhibit expressions of p-ERK1/2, p-p38, MCP-1, VCAM-1 and ICAM-1 in mice aorta. CONCLUSION: α-LNA-LMWCS exhibited anti-atherosclerosis effect through regulating the lipid metabolism and diminishing the synthesis of pro-inflammatory cytokines. The possible mechanism may be that α-LNA-LMWCS could influence MAPK/ NF-κB related signal pathway. GENERAL SIGNIFICANCE: The results may provide significant suggestions for the application of α-LNA-LMWCS in anti-atherosclerosis.
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Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Sulfatos de Condroitina/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aterosclerose/genética , Quimiocina CCL2/metabolismo , Sulfatos de Condroitina/administração & dosagem , Sulfatos de Condroitina/farmacologia , Citocinas/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Ácidos Linolênicos/química , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , NF-kappa B/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Katsuwonus pelamis is a tuna species mostly sold for canned fillets, its livers were lack of utilization. This study thus investigated an oil production method combining microwave (MW) pretreatment and subcritical dimethyl ether (SDME) in aim to reach improved efficiency and oil quality. The heating characteristics from different MW powers (400, 600, and 800 W) were evaluated, and SEM showed MW having hydrolysis effect on matrix lipoprotein, the fortified recovery rate was also found. Under the MW-SDME condition with 600 W power, 1:5 solid-to-liquid ratio, and 100 min, the recovery reached 93.21% in maximal (SDME â¼50%). To further improve quality, MW powers was noticed affecting lipid types, fatty acid composition, and oxidative stability of produced oils. 1286 lipid types (mostly glyceride and phospholipid-type) were identified, while higher MW lowered the emulsifying phospholipids prompting phase separation. Several oxidation indexes consistently increased with the rising MW power, GC-MS suggested 400 W for higher DHA.
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The ability to recover tissue deformation from visual features is fundamental for many robotic surgery applications. This has been a long-standing research topic in computer vision, however, is still unsolved due to complex dynamics of soft tissues when being manipulated by surgical instruments. The ambiguous pixel correspondence caused by homogeneous texture makes achieving dense and accurate tissue tracking even more challenging. In this paper, we propose a novel self-supervised framework to recover tissue deformations from stereo surgical videos. Our approach integrates semantics, cross-frame motion flow, and long-range temporal dependencies to enable the recovered deformations to represent actual tissue dynamics. Moreover, we incorporate diffeomorphic mapping to regularize the warping field to be physically realistic. To comprehensively evaluate our method, we collected stereo surgical video clips containing three types of tissue manipulation (i.e., pushing, dissection and retraction) from two different types of surgeries (i.e., hemicolectomy and mesorectal excision). Our method has achieved impressive results in capturing deformation in 3D mesh, and generalized well across manipulations and surgeries. It also outperforms current state-of-the-art methods on non-rigid registration and optical flow estimation. To the best of our knowledge, this is the first work on self-supervised learning for dense tissue deformation modeling from stereo surgical videos. Our code will be released.
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OBJECTIVE: Segmentation, the partitioning of patient imaging into multiple, labeled segments, has several potential clinical benefits but when performed manually is tedious and resource intensive. Automated deep learning (DL)-based segmentation methods can streamline the process. The objective of this study was to evaluate a label-efficient DL pipeline that requires only a small number of annotated scans for semantic segmentation of sinonasal structures in CT scans. STUDY DESIGN: Retrospective cohort study. SETTING: Academic institution. METHODS: Forty CT scans were used in this study including 16 scans in which the nasal septum (NS), inferior turbinate (IT), maxillary sinus (MS), and optic nerve (ON) were manually annotated using an open-source software. A label-efficient DL framework was used to train jointly on a few manually labeled scans and the remaining unlabeled scans. Quantitative analysis was then performed to obtain the number of annotated scans needed to achieve submillimeter average surface distances (ASDs). RESULTS: Our findings reveal that merely four labeled scans are necessary to achieve median submillimeter ASDs for large sinonasal structures-NS (0.96 mm), IT (0.74 mm), and MS (0.43 mm), whereas eight scans are required for smaller structures-ON (0.80 mm). CONCLUSION: We have evaluated a label-efficient pipeline for segmentation of sinonasal structures. Empirical results demonstrate that automated DL methods can achieve submillimeter accuracy using a small number of labeled CT scans. Our pipeline has the potential to improve pre-operative planning workflows, robotic- and image-guidance navigation systems, computer-assisted diagnosis, and the construction of statistical shape models to quantify population variations. LEVEL OF EVIDENCE: N/A.
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Nano-MoS2 exhibit oxidoreductase-like activities, and has been shown to effectively eliminate excessive intracellular ROS and inhibit Aß aggregation, thus demonstrating promising potential for anti-Alzheimer's disease (anti-AD) intervention. However, the low water dispersibility and high toxicity of nano-MoS2 limits its further application. In this study, we developed a chondroitin sulphate (CS)-modified MoS2 nanoenzyme (CS@MoS2) by harnessing the excellent biocompatibility of CS and the exceptional activities of nano-MoS2 to explore its potential in anti-AD research. Promisingly, CS@MoS2 significantly inhibited Aß1-40 aggregation and prevented toxic injury in SH-SY5Y cells caused by Aß1-40. In addition, CS@MoS2 protected these cells from oxidative stress damage by regulating ROS production, as well as promoting the activities of SOD and GSH-Px. CS@MoS2 also modulated the intracellular Ca2+ imbalance and downregulated Tau hyperphosphorylation by activating GSK-3ß. CS@MoS2 suppressed p-NF-κB (p65) translocation to the nucleus by inhibiting MAPK phosphorylation, and modulated the expression of downstream anti- and proinflammatory cytokines. Owing to its multifunctional activities, CS@MoS2 effectively improved spatial learning, memory, and anxiety in D-gal/AlCl3-induced AD mice. Taken together, these results indicate that CS@MoS2 has significant potential for improving the therapeutic efficacy of the prevention and treatment of AD, while also presenting a novel framework for the application of nanoenzymes.
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Doença de Alzheimer , Sulfatos de Condroitina , Dissulfetos , Molibdênio , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacologia , Animais , Camundongos , Humanos , Molibdênio/química , Molibdênio/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Masculino , Modelos Animais de DoençasRESUMO
OBJECTIVE: Obtaining automated, objective 3-dimensional (3D) models of the Eustachian tube (ET) and the internal carotid artery (ICA) from computed tomography (CT) scans could provide useful navigational and diagnostic information for ET pathologies and interventions. We aim to develop a deep learning (DL) pipeline to automatically segment the ET and ICA and use these segmentations to compute distances between these structures. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. METHODS: From a database of 30 CT scans, 60 ET and ICA pairs were manually segmented and used to train an nnU-Net model, a DL segmentation framework. These segmentations were also used to develop a quantitative tool to capture the magnitude and location of the minimum distance point (MDP) between ET and ICA. Performance metrics for the nnU-Net automated segmentations were calculated via the average Hausdorff distance (AHD) and dice similarity coefficient (DSC). RESULTS: The AHD for the ET and ICA were 0.922 and 0.246 mm, respectively. Similarly, the DSC values for the ET and ICA were 0.578 and 0.884. The mean MDP from ET to ICA in the cartilaginous region was 2.6 mm (0.7-5.3 mm) and was located on average 1.9 mm caudal from the bony cartilaginous junction. CONCLUSION: This study describes the first end-to-end DL pipeline for automated ET and ICA segmentation and analyzes distances between these structures. In addition to helping to ensure the safe selection of patients for ET dilation, this method can facilitate large-scale studies exploring the relationship between ET pathologies and the 3D shape of the ET.
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The purpose of this study was to construct a transmembrane peptide-chondroitin sulphategold nanoparticle (TAT-CS@Au) delivery system and investigate its activity as an anti-Alzheimer's disease (AD) drug. We successfully prepared TAT-CS@Au nanoparticles, investigated their anti-AD effects, and explored the possible mechanisms in in vitro models. TAT-CS@Au exhibited excellent cellular uptake and transport capacity, effectively inhibited the accumulation of Aß1-40, and significantly reduced Aß1-40-induced apoptosis in SH-SY5Y cells. Furthermore, TAT-CS@Au significantly reduced oxidative stress damage and cholinergic injury induced by Aß1-40 by regulating intracellular concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and acetylcholine (ACh). Western blotting results demonstrated that TAT-CS@Au inhibited aberrant tau phosphorylation (Ser199, Thr205, Ser404, and Ser396) through GSK3ß inactivation. TAT-CS@Au decreased the levels of inflammatory factors, specifically TNF-α, IL-6, and IL-1ß, by inhibiting NF-κB nuclear translocation by activating MAPK signalling pathways. Overall, these results indicate that TAT-CS@Au exhibits excellent transmembrane ability, inhibits Aß1-40 accumulation, antagonises oxidative stress, reduces aberrant tau phosphorylation, and suppresses the expression of inflammatory factors. TAT-CS@Au may be a multi-target anti-AD drug with good cell permeability, providing new insights into the design and research of anti-AD therapeutics.
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Doença de Alzheimer , Nanopartículas Metálicas , Neuroblastoma , Humanos , Ouro/farmacologia , Sulfatos de Condroitina/farmacologia , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Estresse OxidativoRESUMO
The BET (bromo and extra-terminal) family proteins are epigenetic readers and master transcription coactivators, which have attracted great interests as cancer therapeutic targets. However, there are few developed labeling toolkits that can be applied for the dynamic studies of BET family proteins in living cells and tissue slices. In order to label and study the distribution of the BET family proteins in tumor cells and tumor tissues, a novel series of environment-sensitive fluorescent probes (6a-6c) were designed and evaluated for their labeling properties. Interestingly, 6a is capable of identifying tumor tissue slices and making a distinction between the tumor and normal tissues. Moreover, it can localize to the nuclear bodies in tumor slices just like BRD3 antibody. In addition, it also played an anti-tumor role through the induction of apoptosis. All these features render 6a may compatible for immunofluorescent studies and future cancer diagnosis, and guide for the discovery of new anticancer drugs.
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Proteínas Nucleares , Fatores de Transcrição , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Apoptose , Proteínas de Ciclo Celular/metabolismoRESUMO
Previous studies have demonstrated that both CS and LiCl possess anti-Alzheimer's disease (AD) activities. We prepared chondroitin sulfate-Li (CS-Li) and investigated its effect on AD and explored the possible mechanisms both in vitro and in vivo. We found that CS-Li could inhibit amyloid ß (Aß) aggregation and protect SH-SY5Y cells from Aß 1-42-induced cytotoxicity in vitro. In D-gal and AlCl3-induced AD mouse model, CS-Li improves the spatial learning and memory abilities of AD mice, reverses the nuclear pyknosis and cell edema, and increases the survival rate of neurons in hippocampus of mice. Moreover, CS-Li significantly increased the levels of GSH-Px, Na+/K+-ATPase, and ChAT and decreased the levels of MDA and AchE in AD mice. Western blot results demonstrated that CS-Li could decrease the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of p-GSK-3ß (Ser9) and PP2A and inhibit the expression of proinflammatory factors through inhibiting NF-κB nuclear translocation by activating the MAPK signaling pathways. In a word, CS-Li can delay AD development through multitarget processes, including Aß aggregation inhibition, oxidative stress damage, tau hyperphosphorylation, and inflammatory response, thereby improves learning and memory abilities.
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Peptídeos beta-Amiloides , Neuroblastoma , Animais , Humanos , Camundongos , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Sulfatos de Condroitina , Glicogênio Sintase Quinase 3 beta , Lítio , Doença de Alzheimer/tratamento farmacológico , Compostos de Alumínio/toxicidadeRESUMO
In the title compound, C(20)H(20)N(2)O(2), the pyrazole ring makes dihedral angles of 15.68â (4) and 83.40â (4)°, respectively, with the tolyl and benzyl rings, respectively.
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Wound dressing composed of polyelectrolyte complexes (PECs), based on chitosan/alginate/hyaluronic acid (CS/ALG/HYA) crosslinked by genipin, was prepared by freeze-dried molding. Genipin as excellent natural biological crosslinker was chose for high biocompatibility and improving mechanical properties of materials. The CS/ALG/HYA sponges (CAHSs) were characterized by FTIR, XRD, DSC and SEM. Porosity, swelling behavior and mechanical properties and in vitro degradation of CAHSs were investigated. The cytotoxicity assay was carried out on HUVEC cells in vitro and the result proves the good biocompatibility of CAHSs. Hemolysis tests indicated that the prepared CAHSs were non-hemolytic material (hemolysis ratio < 5%, no cytotoxicity). PT and aPPT coagulation tests demonstrated that CAHS2 and CAHS3 could both activate the extrinsic and intrinsic coagulation pathway and thus accelerated blood coagulation. Further, in a rat full-thickness wounds model, the CAHS2 sponge significantly facilitates wound closure compared to other groups. CAHSs exhibited adjustable physical, mechanical and biological properties. Thus, the chitosan-based polyelectrolyte composite sponges exhibit great potential as promising wound dressings.
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Alginatos/química , Curativos Biológicos/efeitos adversos , Quitosana/análogos & derivados , Ácido Hialurônico/química , Iridoides/química , Polieletrólitos/química , Animais , Reagentes de Ligações Cruzadas/química , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Nanocompostos/química , Coelhos , Ratos , Ratos WistarRESUMO
Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.
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Antineoplásicos/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Humanos , Neoplasias/tratamento farmacológico , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Proteínas Quinases/farmacologia , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia , Inibidores da Topoisomerase/uso terapêuticoRESUMO
B-cell lymphoma-2 (Bcl-2) proteins family is an essential checkpoint in apoptosis. Extensive evidences suggested that overexpression of anti-apoptotic Bcl-2 proteins can be observed in multiple cancer cell lines and primary tumor biopsy samples, which is an important reason for tumor cells to evade apoptosis and further acquire drug resistance for chemotherapy. Hence, down-regulation of anti-apoptotic Bcl-2 proteins is effective for the treatment of cancers. In view that Bcl-2 inhibitors and some other anti-tumor agents, such as HDAC inhibitors and Mdm2 inhibitors, exert synergy effects in tumor cells, it is pointed out that dual-targeting therapies based on these targets are regarded as rational strategies to enhance the effectiveness of single target agents for cancer treatment. This review briefly introduces the apoptosis, the structure of Bcl-2 family proteins, and focuses on the current status and recent advances of Bcl-2 inhibitors and the corresponding SARs of them. Moreover, we discuss the synergisms between Bcl-2 and other anti-tumor targets, and summarize the current dual-target agents.
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Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quadruplex G , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Relação Estrutura-AtividadeRESUMO
Salbutamol (SBAL), a kind of short-acting beta 2-adrenergic agonist, has been mainly used to treat bronchial asthma and other allergic airway diseases clinically. In this study, the interaction mechanism between salbutamol and human serum albumin was researched by the multispectral method and molecular docking. The fluorescence intensity of HSA could be regularly enhanced with the increase of SBAL concentration. Both the results of the multispectral method and molecular docking showed that SBAL could bind HSA with van der Waals force and hydrogen bonds. The binding mechanism was further analysed by UV-Vis and synchronous fluorescence spectra. The contents of the secondary structure of free HSA and SBAL-HSA complex were evaluated using CD spectra.
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Agonistas de Receptores Adrenérgicos beta 2/química , Albuterol/química , Simulação de Acoplamento Molecular , Albumina Sérica Humana/química , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Humanos , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/efeitos dos fármacosRESUMO
In this study, the effect of chondroitin sulphate nano-selenium (CS@Se) on Alzheimer's disease (AD) in mice was investigated. CS@Se alleviated anxiety and improved the spatial learning and memory impairment in AD mice. CS@Se significantly reduced cell oedema and pyknosis, protected the mitochondria, and improved abnormal changes in the ultrastructure of hippocampal neuron synapses of AD mice. Moreover, CS@Se significantly increased the levels of superoxide dismutase(SOD), glutathione peroxidase (GSH-Px), Na+/K+-ATPase assay (Na+/K+-ATPase) and acetyltransferase (ChAT), and decreased the levels of malondialdehyde (MDA) and acetylcholinesterase (ChAE) in AD mice. Western blot results showed that CS@Se can attenuate excessive phosphorylation of tau (Ser396/Ser404) by regulating the expression of glycogen synthase kinase-3 beta (GSK-3ß). In addition, CS@Se can activate the extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) signalling pathways to inhibit nuclear transcription factor kappa B (NF-κB) nuclear translocation, thereby regulating the expression of pro-inflammatory cytokines. In summary, CS@Se can reduce oxidative stress damage, inhibit excessive tau phosphorylation, reduce inflammation to delay AD development, and increase the learning and memory capacities of AD mice.
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Doença de Alzheimer/tratamento farmacológico , Sulfatos de Condroitina/uso terapêutico , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Selênio/uso terapêutico , Animais , Hipocampo/patologia , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacosRESUMO
The purpose of this study was to ascertain the effect of selenium-chondroitin sulfate nanoparticles (CS@Se) on multi-target-directed therapy for the treatment of Alzheimer's disease (AD). CS@Se nanoparticles were successfully synthesized, and their therapeutic effects were studied in in vitro AD models. CS@Se effectively inhibited amyloid-ß (Aß) aggregation and protected SH-SY5Y cells from Aß1-42-induced cytotoxicity. Moreover, CS@Se significantly decreased okadaic acid-induced actin cytoskeleton instability in SH-SY5Y cells. In addition, CS@Se decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the levels of glutathione peroxidase (GSH-Px). The Western blot results indicated that CS@Se attenuated the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of GSK-3ß. In summary, this study demonstrated that CS@Se could inhibit the aggregation of Aß, reduce damage to the cytoskeleton, mitigate oxidative stress and attenuate the hyperphosphorylation of tau protein. CS@Se might be a potent multi-functional agent for the treatment of AD and thus warrants further research and evaluation.
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Sulfatos de Condroitina , Descoberta de Drogas , Nanopartículas Metálicas , Selênio , Doença de Alzheimer , Amiloide/antagonistas & inibidores , Amiloide/química , Amiloide/ultraestrutura , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Sulfatos de Condroitina/química , Glutationa/metabolismo , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Terapia de Alvo Molecular , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Selênio/química , Análise EspectralRESUMO
Quantitative structure-property relationships (QSPR) were developed to predict the pK(a) values of sulfa drugs via heuristic method (HM) and gene expression programming (GEP). The descriptors of 31 sulfa drugs were calculated by the software CODESSA, which can calculate constitutional, topological, geometrical, electrostatic, and quantum chemical descriptors. HM was also used for the preselection of 4 appropriate molecular descriptors. Linear and nonlinear QSPR models were developed based on the HM and GEP separately and two prediction models lead to a good correlation coefficient (R) of 0.90 and 0.95. The two QSPR models are tseful in predicting pK(a) during the discovery of new drugs and providing theory information for studying the new drugs.
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Algoritmos , Modelos Químicos , Software , Sulfonamidas/química , Expressão Gênica , Relação Quantitativa Estrutura-AtividadeRESUMO
The purpose of this study was to ascertain the effect of chondroitin sulphate-modified doxorubicin (Dox) nanoparticles on enhancing the tumour-targeting effect and tumour growth inhibition effect of doxorubicin both in vitro and in vivo. The chondroitin sulphate-doxorubicin conjugate and its poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CS-Dox-PLGA) were successfully synthesised, and then characterized by Fourier-transform infrared spectroscopy (FTIR), proton magnetic resonance (1HNMR), thermogravimetric analysis/differential scanning calorimetry (TGA/DSC), transmission electron microscope (TEM), zeta potential and laser light scattering. Taking advantage of the enhanced permeability and CD44-mediated endocytosis, CS-Dox-PLGA showed excellent capacity for penetrating the peripheral tumour barrier and into the nucleus of tumour cells. The CS-Dox-PLGA cellular uptake was improved and exhibited a significantly higher level of cytotoxicity in U251 cells. After intravenous administration, the CS-Dox-PLGA showed good pharmacokinetic properties and excellent U251-induced tumour inhibition with low cardiac toxicity. Therefore, CS-Dox-PLGA with low cardiac toxicity and good anti-tumour ability might be a better choice for Dox in clinical practice.