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BACKGROUND: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC. METHODS: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population. RESULTS: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE. CONCLUSIONS: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1.
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Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Hepatite B/complicações , Neoplasias Hepáticas/terapia , Sobrepeso/complicações , Fatores Etários , Índice de Massa Corporal , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica/efeitos adversos , Feminino , Proteína HMGB1/sangue , Hepatite B/sangue , Hepatite B/mortalidade , Vírus da Hepatite B , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Sobrepeso/sangue , Sobrepeso/mortalidade , Veia Porta , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Trombose/complicações , Resultado do TratamentoRESUMO
The mammalian target of rapamycin (mTOR) is a protein kinase that shows key involvement in age-related disease and promises to be a target for treatment of cancer. In the present study, the elimination of potent ATP-competitive mTOR inhibitor 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine (compound 1) is studied in bile duct-cannulated rats, and the metabolism of compound 1 in liver microsomes is compared across species. Compound 1 was shown to undergo extensive N-glucuronidation in bile duct-catheterized rats. N-glucuronides were detected on positions N1 (M2) and N2 (M1) of the pyrazole moiety as well as on the primary amine (M3). All three N-glucuronide metabolites were detected in liver microsomes of the rat, dog, and human, while primary amine glucuronidation was not detected in cynomolgus monkey. In addition, N1- and N2-glucuronidation showed strong species selectivity in vitro, with rat, dog, and human favoring N2-glucuronidation and monkey favoring N1-glucuronide formation. Formation of M1 in monkey liver microsomes also followed sigmoidal kinetics, singling out monkey as unique among the species with regard to compound 1 N-glucuronidation. In this respect, monkeys might not always be the best animal model for N-glucuronidation of uridine diphosphate glucuronosyltransferase (UGT) 1A9 or UGT1A1 substrates in humans. The impact of N-glucuronidation of compound 1 could be more pronounced in higher species such as monkey and human, leading to high clearance in these species. While compound 1 shows promise as a candidate for investigating the impact of pan-mTOR inhibition in vivo, opportunities may exist through medicinal chemistry efforts to reduce metabolic liability with the goal of improving systemic exposure.
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Glucuronídeos/metabolismo , Compostos Heterocíclicos com 2 Anéis/metabolismo , Microssomos Hepáticos/enzimologia , Pirimidinas/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cães , Feminino , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Cinética , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Espectrometria de Massas em TandemRESUMO
RATIONALE: Although Desorption Electrospray Ionization (DESI) Mass Spectrometry Imaging (MSI) is uniquely suited for whole-body (WB) tissue distribution study of drugs, success in this area has been difficult. Here, we present WB tissue distribution studies using DESI-MSI and a new histological tissue-friendly solvent system. METHODS: Neonate pups were dosed subcutaneously (SC) with clozapine, compound 1, compound 2, or compound 3. Following euthanization by hypothermia, neonates underwent a transcardiac perfusion (saline) to remove blood. After cryosectioning, DESI-MSI was conducted for the WB tissue slides, followed sequentially by histological staining. RESULTS: Whole-body tissue imaging showed that clozapine and its N-oxide metabolite were distributed in significant amounts in the brain, spinal cord, liver, heart (ventricle), and lungs. Compound 1 was distributed mainly in the liver and muscle, and its mono-oxygenated metabolite was detected by DESI-MSI exclusively in the liver. Compound 2 was distributed mainly in the muscle and fatty tissue. Compound 3 was distributed mainly in fatty tissue and its metabolites were also mainly detected in the same tissue. CONCLUSIONS: The results demonstrate the successful application of DESI-MSI in whole-body tissue distribution studies of drugs and metabolites in combination with sequential histology staining for anatomy. The results also identified lipophilicity as the driving force in the tissue distribution of the three Amgen compounds.
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Antipsicóticos/farmacocinética , Clozapina/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Imagem Corporal Total/métodos , Animais , Animais Recém-Nascidos , Feminino , Camundongos , Distribuição TecidualRESUMO
Friction as a fundamental physical phenomenon dominates nature and human civilization, among which the achievement of molecular rolling lubrication is desired to bring another breakthrough, like the macroscale design of wheel. Herein, an edge self-curling nanodeformation phenomenon of graphite nanosheets (GNSs) at cryogenic temperature is found, which is then used to promote the formation of graphite nanorollers in friction process towards molecular rolling lubrication. The observation of parallel nanorollers at the friction interface give the experimental evidence for the occurrence of molecular rolling lubrication, and the graphite exhibits abnormal lubrication performance in vacuum with ultra-low friction and wear at macroscale. The molecular rolling lubrication mechanism is elucidated from the electronic interaction perspective. Experiments and theoretical simulations indicate that the driving force of the self-curling is the uneven atomic shrinkage induced stress, and then the shear force promotes the intact nanoroller formation, while the constraint of atomic vibration decreases the dissipation of driving stress and favors the nanoroller formation therein. It will open up a new pathway for controlling friction at microscale and nanostructural manipulation.
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Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.
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Dependovirus , Terapia Genética , Vetores Genéticos , Transgenes , Dependovirus/genética , Humanos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Terapia Genética/métodos , Evasão da Resposta Imune , Animais , Engenharia Genética/métodos , Técnicas de Transferência de Genes , Tropismo ViralRESUMO
Recovery and survival following traumatic brain injury (TBI) depends on optimal amelioration of secondary injuries at lesion site. Delivering mitochondria-protecting drugs to neurons may revive damaged neurons at sites secondarily traumatized by TBI. Pioglitazone (PGZ) is a promising candidate for TBI treatment, limited by its low brain accumulation and poor targetability to neurons. Herein, we report a ROS-responsive nanosystem, camouflaged by hybrid membranes of platelets and engineered extracellular vesicles (EVs) (C3-EPm-|TKNPs|), that can be used for targeted delivery of PGZ for TBI therapy. Inspired by intrinsic ability of macrophages for inflammatory chemotaxis, engineered M2-like macrophage-derived EVs were constructed by fusing C3 peptide to EVs membrane integrator protein, Lamp2b, to confer them with ability to target neurons in inflamed lesions. Platelets provided hybridized EPm with capabilities to target hemorrhagic area caused by trauma via surface proteins. Consequently, C3-EPm-|PGZ-TKNPs| were orientedly delivered to neurons located in the traumatized hemisphere after intravenous administration, and triggered the release of PGZ from TKNPs via oxidative stress. The current work demonstrate that C3-EPm-|TKNPs| can effectively deliver PGZ to alleviate mitochondrial damage via mitoNEET for neuroprotection, further reversing behavioral deficits in TBI mice. Our findings provide proof-of-concept evidence of C3-EPm-|TKNPs|-derived nanodrugs as potential clinical approaches against neuroinflammation-related intracranial diseases.
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Plaquetas , Lesões Encefálicas Traumáticas , Exossomos , Neurônios , Espécies Reativas de Oxigênio , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Plaquetas/metabolismo , Masculino , Exossomos/metabolismo , Camundongos , Peptídeos/administração & dosagem , Peptídeos/química , Camundongos Endogâmicos C57BL , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Sistemas de Liberação de Medicamentos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , BiomiméticaRESUMO
Compound 1 [(E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1S,4S)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide], a new, potent, selective anaplastic lymphoma kinase (ALK) inhibitor with potential application for the treatment of cancer, was selected as candidate to advance into efficacy studies in mice. However, the compound underwent mouse-specific enzymatic hydrolysis in plasma to a primary amine product (M1). Subsequent i.v. pharmacokinetics studies in mice showed that compound 1 had high clearance (CL) and a short half-life. Oral dose escalation studies in mice indicated that elimination of compound 1 was saturable, with higher doses achieving sufficient exposures above in vitro IC(50). Chemistry efforts to minimize hydrolysis resulted in the discovery of several analogs that were stable in mouse plasma. Three were taken in vivo into mice and showed decreased CL corresponding to increased in vitro stability in plasma. However, the more stable compounds also showed reduced potency against ALK. Kinetic studies in NADPH-fortified and unfortified microsomes and plasma produced submicromolar K(m) values and could help explain the saturation of elimination observed in vivo. Predictions of CL based on kinetics from hydrolysis and NADPH-dependent pathways produced predicted hepatic CL values of 3.8, 3.0, 1.6, and 1.2 l/hâ kg for compound 1, compound 2 [(E)-3,5-difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide], compound 3 [(E)-3-chloro-5-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide], and compound 4 [(E)-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-(trifluoromethyl)benzamide], respectively. The in vivo observed CLs for compounds 1, 2, 3, and 4 were 5.52, 3.51, 2.14, and 2.66 l/hâ kg, respectively. These results indicate that in vitro metabolism kinetic data, incorporating contributions from both hydrolysis and NADPH-dependent metabolism, could be used to predict the systemic CL of compounds cleared via hydrolytic pathways provided that the in vitro assays thoroughly investigate the processes, including the contribution of other metabolic pathways and the possibility of saturation kinetics.
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Inibidores de Proteínas Quinases/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Animais , Área Sob a Curva , Cromatografia Líquida , Hidrólise , Concentração Inibidora 50 , Masculino , Camundongos , Inibidores de Proteínas Quinases/sangue , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
Previous game-theoretic studies of vaccination behavior typically have often assumed that populations are homogeneously mixed and that individuals are fully rational. In reality, there is heterogeneity in the number of contacts per individual, and individuals tend to imitate others who appear to have adopted successful strategies. Here, we use network-based mathematical models to study the effects of both imitation behavior and contact heterogeneity on vaccination coverage and disease dynamics. We integrate contact network epidemiological models with a framework for decision-making, within which individuals make their decisions either based purely on payoff maximization or by imitating the vaccination behavior of a social contact. Simulations suggest that when the cost of vaccination is high imitation behavior may decrease vaccination coverage. However, when the cost of vaccination is small relative to that of infection, imitation behavior increases vaccination coverage, but, surprisingly, also increases the magnitude of epidemics through the clustering of non-vaccinators within the network. Thus, imitation behavior may impede the eradication of infectious diseases. Calculations that ignore behavioral clustering caused by imitation may significantly underestimate the levels of vaccination coverage required to attain herd immunity.
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Comportamento de Escolha , Controle de Doenças Transmissíveis/estatística & dados numéricos , Doenças Transmissíveis/epidemiologia , Comportamento Imitativo , Dinâmica Populacional , Comportamento Social , Apoio Social , Simulação por Computador , Humanos , Vacinação em Massa , Modelos EstatísticosRESUMO
Metabolite identification is an important part of the drug discovery and development process. High sensitivity is necessary to identify metabolic products in vitro and in vivo. The most common method utilizes standard high-performance liquid chromatography (4.6 mm i.d. column and 1 mL/min flow rate) coupled to tandem mass spectrometry (HPLC/MS/MS). We have developed a method that utilizes a nano-LC system coupled to a high-resolution tandem mass spectrometer to identify metabolites from in vitro and in vivo samples. Using this approach, we were able to increase the sensitivity of analysis by approximately 1000-fold over HPLC/MS. In vitro samples were analyzed after simple acetonitrile precipitation, centrifugation, and dilution. The significant improvement in sensitivity enabled us to conduct experiments at very low substrate concentrations (0.01 µM), and very low incubation volumes (20 µL). In vivo samples were injected after simple dilution without any pre-purification. All the metabolites identified by conventional HPLC/MS/MS were also identified using the nano-LC method. This study demonstrates a very sensitive approach to identifying phase I and II metabolites with throughput and separation equivalent to the standard HPLC/MS/MS method.
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Cromatografia Líquida de Alta Pressão/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Haplorrinos , Camundongos , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/química , Ratos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.
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Inibidores de Proteínas Quinases/química , Piridazinas/química , Piridinas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Benzimidazóis/química , Sítios de Ligação , Ligação Competitiva , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Imidazóis/química , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridazinas/síntese química , Piridazinas/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
As a part of the multi-source cooperative navigation scheme, data fusion has a significant impact on the quality of state estimation. Particle filtering has gradually become the focus of many fusion methods due to its unique theoretical advantages in nonlinear non-Gaussian systems. However, the particle degradation and the resulting sample impoverishment restrict its application in complex engineering scenarios. In this paper, a robust cubature fission particle filter (RCFPF) is proposed to deal with these problems. First, in the framework of cubature rule, Huber function is used to combine the L2 norm and L1 norm to improve the importance density function(IDF), suppress the observation noise. Meanwhile, the proposed distribution(PD) is further optimized by combining the Gaussian distribution with Laplace distribution to alleviate particle degradation. Second, the particle swarm is fissioned before resampling, and the particle weight is reconstructed by fission of high weight particles and covering low weight particles to inhibit sample impoverishment. The vehicle experiments of multi-source cooperative navigation show that the proposed algorithm achieves better test results in accuracy and robustness than extended Kalman filter (EKF), strong tracking particle filter (STPF), and cubature particle filter (CPF).
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Crises-such as the COVID-19 pandemic-bring about myriad problems in magnitude (severity), dynamism (quality), and urgency (timing). Collaborative models that bring together actors from both the public and private sector have thus emerged for institutionalized and community-based crisis response. Such models aim particularly to reach vulnerable, hard-to-reach communities, such as racialized immigrant communities that are among those disproportionately impacted at times of crisis. This paper presents a case study of a community-based, cross-sectoral collaborative formed to respond to the COVID-19 pandemic and specifically targeting immigrant communities. Findings inform a conceptual framework that illustrates the integration of two spheres of service: crisis supports, characterized by a short-term approach, broad-based reach and general objectives; and settlement supports, characterized by their long-term approach, trust relations and targeted objectives, such as language supports and culturally appropriate outreach.
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The low survival rate of hepatocellular carcinoma (HCC) remains a major challenge for clinicians and patients, and its progression may be related to hypoxia-inducible factor (HIF) and PD-L1. LW6 is a drug that inhibits hypoxia by reducing HIF-1α accumulation and gene transcriptional activity. However, its effect and regulatory mechanism in HCC remain to be revealed, especially under hypoxic conditions. The HIF-1α and PD-L1 expression in HCC specimens and paracarcinoma tissues was evaluated by a tissue microarray (TMA). The effects of LW6 were evaluated by cell viability, colony formation, and Transwell assays and xenografted nude mice. Cell cycle and apoptosis of HCC cells were detected by flow cytometry. The effects of LW6 on HIF-1α signaling and its targets PD-L1 and VEGF were evaluated through qRT-PCR, Western blots, Cell transfection, Transwell migration and invasion assays, immunohistochemistry, immunofluorescence and luciferase assays. In this study, we found that LW6 had antiproliferative effects on HCC and promoted HCC cell apoptosis, inhibited their migration and invasion, and affected their cell cycle. LW6 dramatically decreased HIF-1α expression through the VHL-dependent proteasome system pathway, inhibited HIF-1α transcriptional activation, and reduced PD-L1 expression by inhibiting EGFR pathway activation. These results suggest that LW6 can promote apoptosis of HCC cells by inhibiting HIF-1α, inhibit tumor angiogenesis, and downregulate the expression of PD-L1, which is an effective choice for the treatment of HCC. Moreover, inhibiting the hypoxic microenvironment combined with immunotherapy is expected to be a potentially effective strategy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Microambiente TumoralRESUMO
Inside a spacecraft, the temperature and humidity, suitable for the human crew onboard, also creates an ideal breeding environment for the proliferation of bacteria and fungi; this can present a hazard to human health and create issues for the safe running of equipment. To address this issue, wear-resistant antimicrobial thin films prepared by magnetron sputtering were developed, with the aim to coat key internal components within spacecrafts. Silver and copper are among the most studied active bactericidal materials, thus this work investigated the antibacterial properties of amorphous carbon coatings, doped with either silver, silver and copper, or with silver clusters. The longevity of these antimicrobial coatings, which is heavily influenced by metal diffusion within the coating, was also investigated. With a conventional approach, amorphous carbon coatings were prepared by cosputtering, to generate coatings that contained a range of silver and copper concentrations. In addition, coatings containing silver clusters were prepared using a separate cluster source to better control the metal particle size distribution in the amorphous carbon matrix. The particle size distributions were characterized by grazing-incidence small-angle X-ray scattering (GISAXS). Antibacterial tests were performed under both terrestrial gravity and microgravity conditions, to simulate the condition in space. Results show that although silver-doped coatings possess extremely high levels of antimicrobial activity, silver cluster-doped coatings are equally effective, while being more long-lived, despite containing a lower absolute silver concentration.
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Anti-Infecciosos , Materiais Revestidos Biocompatíveis , Envelhecimento , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Carbono , Materiais Revestidos Biocompatíveis/farmacologia , HumanosRESUMO
Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. STATEMENT OF SIGNIFICANCE: TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo.
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Lesões Encefálicas Traumáticas , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Biomimética , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Camundongos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction. In vivo pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover, in vivo imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.
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COVID-19 , Quitosana , Nanopartículas , Preparações Farmacêuticas , Animais , Eritrócitos , Humanos , Pulmão , Metilprednisolona , Ratos , SARS-CoV-2RESUMO
Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery.
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Tratamento Farmacológico da COVID-19 , Nanopartículas , Eritrócitos , Humanos , Ivermectina , Pulmão , SARS-CoV-2RESUMO
BACKGROUND: A group of substituted benzothiazoles from a research project was found to have low microsomal clearance. However, these compounds had very high clearance in vivo. METHODS: In the present study, the clearance mechanism of two of the structural analogs, was investigated in vitro and in vivo. RESULTS: In vitro studies showed the formation of corresponding non-P450 dependent oxidative metabolites in S9, cytosol, and hepatocytes. The in vitro formation of these metabolites was observed in mice, rats, non-human primates, and humans. The dog did not form the corresponding metabolites in any of the matrices. Inhibition studies with S9 fraction and incubation with human recombinant aldehyde oxidase (AO) showed that the formation of the corresponding metabolites was AO dependent. To investigate the role of this pathway in vivo, mice were dosed with compound A and bile and plasma were analyzed. Most of the metabolites in bile contained the AO-dependent oxidized benzothiazole moiety, indicating that metabolism involving AO was probably the main pathway for clearance. The same metabolites were also observed circulating in plasma. Mass spectrometric analysis of the metabolite showed that the oxidation was on the benzothiazole moiety, but the exact position could not be identified. Isolation of the metabolite of compound A and analysis by NMR confirmed the structure of the metabolite as C2 carbon oxidation of the thiazole ring resulting in carboxamide moiety. Further comparison of both metabolites with corresponding authentic standards confirmed the structures. CONCLUSION: To our knowledge, such an observation of in vitro and in vivo oxidation of substituted benzothiazole by AO has not been reported before. The results helped the medicinal chemists design compounds that avoid AO-mediated metabolism and with better ADME property.
Assuntos
Aldeído Oxidase , Hepatócitos , Aldeído Oxidase/metabolismo , Animais , Benzotiazóis/metabolismo , Cães , Hepatócitos/metabolismo , Cinética , Taxa de Depuração Metabólica , Camundongos , Microssomos Hepáticos/metabolismo , RatosRESUMO
Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.
Assuntos
Antídotos/farmacologia , Materiais Biomiméticos/metabolismo , Cromo/intoxicação , Membrana Eritrocítica/metabolismo , Nanopartículas/química , Succímero/farmacologia , Animais , Antídotos/administração & dosagem , Antídotos/farmacocinética , Química Farmacêutica , Portadores de Fármacos , Liberação Controlada de Fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Tamanho da Partícula , Células RAW 264.7 , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Succímero/administração & dosagem , Succímero/farmacocinéticaRESUMO
OBJECTIVES: This retrospective cohort study investigated the efficacy of routine intravenous chemotherapy (the control group), transcatheter arterial infusion (TAI) chemotherapy, and TAI combined with radioactive particles as therapeutic methods for advanced body/tail pancreatic cancer by assessing the short-term and overall survival rates. METHODS: We screened our prospective database for patients with advanced body/tail pancreatic cancer, which tumor deemed unresectable, and no other confirmed malignant tumors, patients were assigned into 3 groups according to their treatment: routine intravenous chemotherapy, TAI, and TAI combined with radioactive particles. RESULTS: The median survival time was 6 months in the control group, 10 months in the TAI group, and 13 months in the TAI combined group. The Kaplan-Meier estimates of the overall survival among the 3 groups, indicating that there is significant difference among 3 groups (P < 0.000). The clinical remission rates were 17.5% in the control group, 41.5% in the TAI group, and 48.0% in the TAI combined group. Covariates analyzed showed that different treatment methods and times affected the results significantly (P < 0.002). CONCLUSIONS: In the treatment of advanced body/tail pancreatic cancer, TAI and TAI combined with radioactive particles significantly improved the clinical outcomes in patients compared with routine intravenous chemotherapy.