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1.
J Mater Chem B ; 9(38): 8121-8137, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34494632

RESUMO

The delayed healing of infected post-operative wounds has turned into a worldwide medical problem. In the clinical treatment, effective bacterial clearance and promoted wound healing were considered as two crucial aspects. However, the effect of current dressings with antibacterial activity was limited due to the declined efficacy against antibiotic-resistant bacteria, and poor mechanical property during skin extension and compression movement. In this project, a lyotropic liquid crystal (LLC)-based bacteria-resistant and self-healing spray dressing loaded with ε-polylysine (PLL) was designed. Owing to the unique antibacterial mechanism, PLL was expected to kill antibiotic-resistant bacteria efficiently, even the "superbug" methicillin-resistant Staphylococcus aureus (MRSA). The cubic cells of LLC were applied to encapsulate PLL to improve its stability and induce a sustained release, further realizing a long-term antibacterial effect. Meanwhile, the LLC precursor (LLCP) could extend to the irregular edges of the wound, and spontaneously transited to a cubic phase gel once exposed to physiological fluid. This 3D structure was also endowed with mechanically responsive viscoelasticity that formed a robust and flexible defense for wounds. An excellent antibacterial activity with more than 99% MRSA killed in 3 h was demonstrated by a killing kinetics study. The long-term effect was also proved by measuring the bacteriostatic circle test within 48 h. In addition, the unique sol-gel phase transition behavior and superior self-healing capacity of PLL-LLCP was verified with the rheological study and self-recoverable conformal deformation test in vivo. In the infected post-operative wound model, satisfactory bacterial clearance and prominent wound healing promotion were realized by PLL-LLCP, with the survival of the bacteria at lower than 0.1% and the wound closure at higher than 90%. Thus, PLL-LLCP was believed to be an excellent candidate for the therapy of infected post-operative wounds.

2.
Cell Rep ; 36(11): 109698, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525349

RESUMO

Human hematopoiesis is a dynamic process that starts in utero 18-21 days post-conception. Understanding the site- and stage-specific variation in hematopoiesis is important if we are to understand the origin of hematological disorders, many of which occur at specific points in the human lifespan. To unravel how the hematopoietic stem/progenitor cell (HSPC) compartment changes during human ontogeny and the underlying gene regulatory mechanisms, we compare 57,489 HSPCs from 5 different tissues spanning 4 developmental stages through the human lifetime. Single-cell transcriptomic analysis identifies significant site- and developmental stage-specific transitions in cellular architecture and gene regulatory networks. Hematopoietic stem cells show progression from cycling to quiescence and increased inflammatory signaling during ontogeny. We demonstrate the utility of this dataset for understanding aberrant hematopoiesis through comparison to two cancers that present at distinct time points in postnatal life-juvenile myelomonocytic leukemia, a childhood cancer, and myelofibrosis, which classically presents in older adults.

4.
Nat Commun ; 12(1): 4725, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354051

RESUMO

Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Antibacterianos/administração & dosagem , Ceco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Vida Livre de Germes , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Termogênese/fisiologia , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
5.
Nat Commun ; 12(1): 4797, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376651

RESUMO

Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. The coronal suture is most commonly fused in monogenic craniosynostosis, yet the unique aspects of its development remain incompletely understood. To uncover the cellular diversity within the murine embryonic coronal suture, we generated single-cell transcriptomes and performed extensive expression validation. We find distinct pre-osteoblast signatures between the bone fronts and periosteum, a ligament-like population above the suture that persists into adulthood, and a chondrogenic-like population in the dura mater underlying the suture. Lineage tracing reveals an embryonic Six2+ osteoprogenitor population that contributes to the postnatal suture mesenchyme, with these progenitors being preferentially affected in a Twist1+/-; Tcf12+/- mouse model of Saethre-Chotzen Syndrome. This single-cell atlas provides a resource for understanding the development of the coronal suture and the mechanisms for its loss in craniosynostosis.


Assuntos
Suturas Cranianas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Osteogênese/genética , Análise de Célula Única/métodos , Transcriptoma/genética , Acrocefalossindactilia/embriologia , Acrocefalossindactilia/genética , Acrocefalossindactilia/patologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Suturas Cranianas/citologia , Suturas Cranianas/embriologia , Dura-Máter/citologia , Dura-Máter/embriologia , Dura-Máter/metabolismo , Mesoderma/citologia , Mesoderma/embriologia , Mesoderma/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Osteoblastos/citologia , Osteoblastos/metabolismo , RNA-Seq/métodos , Crânio/citologia , Crânio/embriologia , Crânio/metabolismo , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo
7.
Cell Metab ; 33(5): 888-904.e6, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33667386

RESUMO

The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.

8.
J Exp Med ; 218(2)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416891

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a "first hit," (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.


Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia Mielomonocítica Juvenil/patologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/genética , Masculino , Camundongos , Mutação/genética , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/genética , Regulação para Cima/genética
10.
Acta Pharm Sin B ; 10(7): 1331-1346, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32874832

RESUMO

An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values (R 2 = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32854265

RESUMO

Major public health incidents such as COVID-19 typically have characteristics of being sudden, uncertain, and hazardous. If a government can effectively accumulate big data from various sources and use appropriate analytical methods, it may quickly respond to achieve optimal public health decisions, thereby ameliorating negative impacts from a public health incident and more quickly restoring normality. Although there are many reports and studies examining how to use big data for epidemic prevention, there is still a lack of an effective review and framework of the application of big data in the fight against major public health incidents such as COVID-19, which would be a helpful reference for governments. This paper provides clear information on the characteristics of COVID-19, as well as key big data resources, big data for the visualization of pandemic prevention and control, close contact screening, online public opinion monitoring, virus host analysis, and pandemic forecast evaluation. A framework is provided as a multidimensional reference for the effective use of big data analytics technology to prevent and control epidemics (or pandemics). The challenges and suggestions with respect to applying big data for fighting COVID-19 are also discussed.


Assuntos
Big Data , Infecções por Coronavirus , Ciência de Dados , Pandemias , Pneumonia Viral , Saúde Pública/métodos , Betacoronavirus , COVID-19 , Humanos , SARS-CoV-2
12.
Mol Cell ; 78(3): 477-492.e8, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386542

RESUMO

Myelofibrosis is a severe myeloproliferative neoplasm characterized by increased numbers of abnormal bone marrow megakaryocytes that induce fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed single-cell transcriptome profiling of 135,929 CD34+ lineage- hematopoietic stem and progenitor cells (HSPCs), single-cell proteomics, genomics, and functional assays. We identified a bias toward megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkPs) are transcriptionally similar to healthy-donor MkPs, but the majority are disease specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs have increased expression of megakaryocyte-associated genes compared to wild-type HSPCs, and we provide early validation of G6B as a potential immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.


Assuntos
Hematopoese/fisiologia , Megacariócitos/patologia , Mielofibrose Primária/sangue , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Regulação da Expressão Gênica , Hematopoese/genética , Células-Tronco Hematopoéticas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Megacariócitos/fisiologia , Pessoa de Meia-Idade , Mutação , Receptores Imunológicos/genética , Análise de Célula Única/métodos
13.
Pharm Dev Technol ; 25(7): 899-907, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32324081

RESUMO

Calcitriol, as the biologically active form of vitamin D3, is essential for patients with renal osteopathy. The solubilization, stabilization, and content uniformity are key issues in its formulation development. In our previous study, the incomplete release of calcitriol was solved by using the hybrid lipid-based solid dispersion (SD) for calcitriol. However, good stability and content uniformity are still urgently needed. In this study, solid lipid with antioxidant properties and liquid lipid compatible with calcitriol were employed as hybrid lipid carrier (HLC) to establish a solid dispersion. Moreover, the content uniformity of tablets with hybrid lipid carrier based SDs (HLCTs) was further guaranteed due to the multi-dispersion of calcitriol in HLC, solidification, and blank granules. Additionally, the compression of the blank granules was adjusted by the water content. The mixing method of calcitriol-containing and blank granules was also optimized. The obtained HLCTs were evaluated for hardness, disintegration time, in vitro drug dissolution, content uniformity, and stability. Satisfactory HLCTs were developed successfully in this study with superior content uniformity and better stability than the commercial soft capsule (Rocaltrol®). It was proved to be a promising formulation for drugs with poor water-solubility, instability to oxygen and heat, and dose-related toxicity.


Assuntos
Conservadores da Densidade Óssea/síntese química , Calcitriol/síntese química , Portadores de Fármacos/síntese química , Composição de Medicamentos/métodos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacocinética , Calcitriol/administração & dosagem , Calcitriol/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Estabilidade de Medicamentos , Comprimidos
14.
J Pharm Sci ; 109(5): 1692-1702, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31987851

RESUMO

For carrier-based dry-powder inhaler (DPI) formulations, the adhesion between carrier particles and active pharmaceutical ingredients (API) particles have a significant influence on the aerosolization performance of the API-carrier complexes and the desired detachment of the API for efficient pulmonary delivery. In our previous study, nanoporous mannitol material was successfully fabricated as carriers by a one-step nonorganic solvent spray drying method with the thermal degradation of ammonium carbonate. These carriers were shown to achieve excellent aerosolization performance. In addition, no residue of ammonium carbonate was detected on the powder surface. However, the safety of nanoporous mannitol carriers (Nano-PMCs) during pulmonary administration/delivery was still unknown because the lung is vulnerable to the inhaled particles. To address this question, the present study was conducted to construct a systematic safety evaluation for DPIs carriers to investigate the safety of Nano-PMCs in the whole inhalation, which would make up for the lack of detailed and standardized method in this field. In vitro safety evaluation was carried out using respiratory and pulmonary cytotoxicity tests, hemolysis assay, and ciliotoxicity test. In vivo safety evaluation was studied by measuring inflammatory indicators in the bronchoalveolar lavage fluid, assessing the pulmonary function and observing pulmonary pathological changes. Nano-PMCs showed satisfactory biocompatibility on respiratory tracts and lungs in vitro and in vivo. It was suggested that Nano-PMCs were safe for intrapulmonary delivery and potential as DPI carriers.


Assuntos
Manitol , Nanoporos , Administração por Inalação , Aerossóis/toxicidade , Portadores de Fármacos , Inaladores de Pó Seco , Manitol/toxicidade , Tamanho da Partícula , Pós
16.
J Dairy Sci ; 102(7): 6056-6064, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079910

RESUMO

Hypocalcemia is a common postpartum condition in dairy cows, which negatively affects health and production. Intravenous Ca infusions are commonly included in calving protocols to prevent or mitigate the effect of hypocalcemia in multiparous cows. Thus, we sought to contrast the effect of intravenous Ca infusion against voluntary oral Ca intake on Ca metabolism. Serum total Ca (tCa) and whole-blood ionized Ca (iCa) were monitored in 24 multiparous Holstein cows after parturition. Precalving diets were formulated with a positive dietary cation-anion difference of 172 mEq/kg of DM and contained 4.1 g of Ca/kg of DM. At parturition, cows were blocked by calving sequence and calcemic status as either normocalcemic (cutoff threshold of iCa ≥1.10 mmol/L) or hypocalcemic (cutoff threshold of iCa <1.10 mmol/L). Cows in each block were randomly assigned to 1 of 2 treatments: either an oral source of Ca (Ca-Oral; n = 12) or an intravenous source of Ca (Ca-IV; n = 12). Cows in the Ca-Oral group were offered a 20-L commercial Ca suspension (48 g of Ca) for voluntary consumption. The supplement contained Ca carbonate, Ca formate, Ca propionate, and other minerals and vitamins (Farm-O-San Reviva, Trouw Nutrition, Amersfoort, the Netherlands). Cows in the Ca-IV group received a 450-mL intravenous Ca solution (13 g of Ca) that contained 298 mg/mL of Ca gluconate, 33 mg/mL of magnesium chloride, and 82 mg/mL of boric acid (AmosCAL, Kommer-Biopharm BV, Heiloo, the Netherlands). Both treatments were initiated within 25 ± 10 min after calving. The oral Ca suspension was offered to cows in a 25-L bucket and was available for 10 min. All cows in the Ca-Oral group voluntarily consumed the entire 20 L of the Ca suspension within 5 min. Blood samples for Ca analyses were collected at 0 (before treatment initiation), 1, 3, 10, and 18 h relative to treatment, and at 0700 and 1900 h for the next 2 consecutive days, to represent the 24-, 36-, 48-, and 60-h sampling time points. In Ca-IV cows, both iCa and tCa concentrations peaked at 1 h (1.54 mmol/L for iCa and 2.85 mmol/L for tCa) and declined to a nadir at 24 h following treatment initiation (0.94 mmol/L for iCa and 1.74 mmol/L for tCa). Although whole-blood iCa and serum tCa were higher at 1 and 3 h in Ca-IV cows, concentrations of iCa were greater for Ca-Oral cows at 18, 24, and 36 h and for tCa at 24 and 36 h. Our data indicate that intravenous Ca infusion immediately induced a state of hypercalcemia followed by lower whole-blood iCa and serum tCa concentrations 24 h later compared with oral Ca.


Assuntos
Cálcio/administração & dosagem , Doenças dos Bovinos/prevenção & controle , Homeostase/efeitos dos fármacos , Hipocalcemia/veterinária , Administração Intravenosa/veterinária , Animais , Cálcio/sangue , Cálcio na Dieta/administração & dosagem , Bovinos , Doenças dos Bovinos/sangue , Dieta/veterinária , Feminino , Hipocalcemia/prevenção & controle , Lactação , Países Baixos , Parto , Gravidez , Distribuição Aleatória
17.
Cell Rep ; 26(10): 2720-2737.e5, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30840893

RESUMO

The relation between gut microbiota and the host has been suggested to benefit metabolic homeostasis. Brown adipose tissue (BAT) and beige adipocytes facilitate thermogenesis to maintain host core body temperature during cold exposure. However, the potential impact of gut microbiota on the thermogenic process is confused. Here, we evaluated how BAT and white adipose tissue (WAT) responded to temperature challenges in mice lacking gut microbiota. We found that microbiota depletion via treatment with different cocktails of antibiotics (ABX) or in germ-free (GF) mice impaired the thermogenic capacity of BAT by blunting the increase in the expression of uncoupling protein 1 (UCP1) and reducing the browning process of WAT. Gavage of the bacterial metabolite butyrate increased the thermogenic capacity of ABX-treated mice, reversing the deficit. Our results indicate that gut microbiota contributes to upregulated thermogenesis in the cold environment and that this may be partially mediated via butyrate.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Microbiota/fisiologia , Termogênese/fisiologia , Proteína Desacopladora 1/metabolismo , Animais , Temperatura Baixa , Humanos , Masculino , Camundongos
18.
ACS Appl Mater Interfaces ; 11(1): 176-186, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525386

RESUMO

The blood-brain tumor barrier (BTB) and blood-brain barrier (BBB) have always been the major barriers in glioma therapy. In this report, we proposed D-T7 peptide-modified nanoparticles actively targeted glioma by overcoming the BBB and BTB to improve the antiglioma efficacy. Glioma-targeting experiments showed that the penetration effect of the D-T7 peptide-modified nanoparticles was 7.89-fold higher than that of unmodified nanoparticles. Furthermore, cediranib (CD) and paclitaxel (PTX) were used for the combination of the antiangiogenesis and chemotherapy for glioma. PEGylated bilirubin nanoparticles (BRNPs) were selected as a suitable drug delivery system (CD&PTX@TBRBPs) owing to the antioxidant, anti-inflammatory, and reactive oxygen species-responsive ability. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assays showed that CD&PTX@TBRBPs had the highest cytotoxicity and the median survival time of the CD&PTX@TBRNP group was 3.31-fold and 1.23-fold longer than that of the saline and CD&PTX@BRNP groups, respectively. All the results showed that we constructed a novel and accessible peptide-modified dual drug carrier with an enhanced antiglioma effect.


Assuntos
Bilirrubina , Neoplasias Encefálicas , Colágeno Tipo IV , Portadores de Fármacos , Glioma , Nanopartículas , Paclitaxel , Fragmentos de Peptídeos , Quinazolinas , Animais , Bilirrubina/química , Bilirrubina/farmacologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Colágeno Tipo IV/química , Colágeno Tipo IV/farmacocinética , Colágeno Tipo IV/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/farmacologia , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia
19.
Pharmaceutics ; 10(4)2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30513738

RESUMO

Netilmicin (NTM) is one of the first-line drugs for lower respiratory tract infections (LRTI) therapy, but its nephrotoxicity and ototoxicity caused by intravenous injection restrict its clinical application. Dry powder inhalation (DPI) is a popular local drug delivery system that is introduced as a solution. Due to the nature of NTM hygroscopicity that hinders its direct use through DPI, in this study, L-leucine (LL) was added into NTM dry powder to reduce its moisture absorption rate and improve its aerosolization performance. NTM DPIs were prepared using spray-drying with different LL proportions. The particle size, density, morphology, crystallinity, water content, hygroscopicity, antibacterial activity, in vitro aerosolization performance, and stability of each formulation were characterized. NTM DPIs were suitable for inhalation and amorphous with a corrugated surface. The analysis indicated that the water content and hygroscopicity were decreased with the addition of LL, whilst the antibacterial activity of NTM was maintained. The optimal formulation ND2 (NTM:LL = 30:1) showed high fine particle fraction values (85.14 ± 8.97%), which was 2.78-fold those of ND0 (100% NTM). It was stable after storage at 40 ± 2 °C, 75 ± 5% relative humidity (RH). The additional LL in NTM DPI successfully reduced the hygroscopicity and improved the aerosolization performance. NTM DPIs were proved to be a feasible and desirable approach for the treatment of LRTI.

20.
Int J Mol Sci ; 19(10)2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30274263

RESUMO

Naphthyridine derivatives are a widely-used class of heterocycles due to their pharmacological activities. A novel compound (10-Methoxy-1,2,3,4-tetrahydrobenzo(g)(1,3) diazepino(1,2-a)-(1,8)naphthyridin-6-yl)(phenyl) methanone (named 3u), showed good anticancer activity in the human malignant melanoma cell line A375 via Thiazolyl Blue Tetrazolium Bromide (MTT) assay. After Western blotting confirmed, we found that 3u induces necroptosis at low concentrations and apoptosis at high concentrations via the upregulation of death receptors and scaffold protein in A375 cells. Furthermore, by combining 3u with the caspase inhibitor zVAD-fmk or Receptor Interacting Serine/Threonine Kinase 1 (RIP1) kinase inhibitor Necrostatin-1 (Nec-1), we found that the activity of caspase-8 was the crucial factor that determined whether either apoptosis or necroptosis occurred. The results indicate that 3u should be considered as a potential chemical substance for melanoma treatment.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Melanoma/metabolismo , Naftiridinas/química , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos
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