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1.
Plant Cell Environ ; 45(6): 1682-1697, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35297062

RESUMO

Using a population of recombinant inbred lines (RILs) cowpea (Vigna unguiculata. L. Walp), we tested for co-linkages between lipid contents and chilling responses of photosynthesis. Under low-temperature conditions (19°C/13°C, day/night), we observed co-linkages between quantitative trait loci intervals for photosynthetic light reactions and specific fatty acids, most strikingly, the thylakoid-specific fatty acid 16:1Δ3trans found exclusively in phosphatidylglycerol (PG 16:1t). By contrast, we did not observe co-associations with bulk polyunsaturated fatty acids or high-melting-point-PG (sum of PG 16:0, PG 18:0 and PG 16:1t) previously thought to be involved in chilling sensitivity. These results suggest that in cowpea, chilling sensitivity is modulated by specific lipid interactions rather than bulk properties. We were able to recapitulate the predicted impact of PG 16:1t levels on photosynthetic responses at low temperature using mutants and transgenic Arabidopsis lines. Because PG 16:1t synthesis requires the activity of peroxiredoxin-Q, which is activated by H2 O2 and known to be involved in redox signalling, we hypothesise that the accumulation of PG 16:1t occurs as a result of upstream effects on photosynthesis that alter redox status and production of reactive oxygen species.

2.
Drug Deliv ; 28(1): 2534-2547, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34854788

RESUMO

Liver fibrosis is a major global health concern. Management of chronic liver disease is severely restricted in clinics due to ineffective treatment approaches. However, a lack of targeted therapy may aggravate this condition. Asiatic acid (AA), a pentacyclic triterpenoid acid, can effectively protect the liver from hepatic disorders. However, the pharmaceutical application of AA is limited by low oral bioavailability and poor targeting efficiency. This study synthesized a novel liver-targeting material from PEG-SA, chemically linked to ursodeoxycholic acid (UA), and utilized it to modify AA nanostructured lipid carriers (UP-AA-NLC) with enhanced targeting and improved efficacy. The formulation of UP-AA-NLC was optimized via the Box-Behnken Experimental Design (BBD) and characterized by size, zeta potential, TEM, DSC, and XRD. Furthermore, in vitro antifibrotic activity and proliferation of AA and NLCs were assessed in LX-2 cells. The addition of UP-AA-NLC significantly stimulated the TGF-beta1-induced expression of α-SMA, FN1, and Col I α1. In vivo near-infrared fluorescence imaging and distribution trials in rats demonstrated that UP-AA-NLC could significantly improve oral absorption and liver-targeting efficiency. Oral UP-AA-NLC greatly alleviated carbon tetrachloride-induced liver injury and fibrosis in rats in a dosage-dependent manner, as reflected by serum biochemical parameters (AST, ALT, and ALB), histopathological features (H&E and Masson staining), and antioxidant activity parameters (SOD and MDA). Also, treatment with UP-AA-NLC lowered liver hydroxyproline levels, demonstrating a reduction of collagen accumulation in the fibrotic liver. Collectively, optimized UP-AA-NLC has potential application prospects in liver-targeted therapy and holds great promise as a drug delivery system for treating liver diseases.


Assuntos
Cirrose Hepática/tratamento farmacológico , Nanoestruturas/química , Triterpenos Pentacíclicos/farmacologia , Animais , Tetracloreto de Carbono/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Lipídeos/química , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tamanho da Partícula , Triterpenos Pentacíclicos/administração & dosagem , Triterpenos Pentacíclicos/farmacocinética , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Ácido Ursodesoxicólico/química
3.
J Exp Clin Cancer Res ; 40(1): 345, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732230

RESUMO

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play critical roles in many biological processes and developmental functions. Chromosomal translocation of FGFRs result in the formation of chimeric FGFR fusion proteins, which often cause aberrant signaling leading to the development and progression of human cancer. Due to the high recurrence rate and carcinogenicity, oncogenic FGFR gene fusions have been identified as promising therapeutic targets. Erdafitinib and pemigatinib, two FGFR selective inhibitors targeting FGFR fusions, have been approved by the U.S. Food and Drug Administration (FDA) to treat patients with urothelial cancer and cholangiocarcinoma, respectively. Futibatinib, a third-generation FGFR inhibitor, is under phase III clinical trials in patients with FGFR gene rearrangements. Herein, we review the current understanding of the FGF/FGFRs system and the oncogenic effect of FGFR fusions, summarize promising inhibitors under clinical development for patients with FGFR fusions, and highlight the challenges in this field.


Assuntos
Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos
5.
Pharm Dev Technol ; 26(9): 943-952, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34372745

RESUMO

Oral absorption of peptides/proteins is usually compromised by various gastrointestinal tract barriers. To improve delivery efficiency, chitosan-conjugated deoxycholic acid (CS-DCA) coupled with sodium alginate (ALG) was prepared to load insulin into pH-sensitive nanoparticles. The insulin-loaded chitosan-deoxycholic acid/alginate nanoparticles (CDA NPs) were characterized by size (143.3 ± 10.8 nm), zeta potential (19.5 ± 1.6 mV), entrapment efficiency (61.14 ± 1.67%), and insulin drug loading (3.36 ± 0.09%). The CDA NPs exhibited pH-triggered release characteristics in vitro and protected the wrapped insulin from gastric degradation. Stability of the CDA NPs in enzyme-containing simulated gastrointestinal fluids suggested that the NPs could partially protect the wrapped insulin from enzymatic degradation. Additionally, CS-DCA-modified NPs promoted the permeability of Caco-2 cells and enhanced intracellular absorption of FITC-labeled insulin by 9.4 and 1.2-folds, when compared to insulin solution and unmodified NPs, respectively. The positively charged NPs increased intestinal villi adhesion and enhanced insulin absorption in the intestines of diabetic rat models. Furthermore, the hypoglycemic test showed that CDA NPs prolonged insulin release in vivo and exerted a remarkable hypoglycemic effect on diabetic rats with an oral bioavailability of 15%. In conclusion, CDA NPs is a potential oral insulin delivery system.


Assuntos
Alginatos/administração & dosagem , Quitosana/administração & dosagem , Ácido Desoxicólico/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Insulina/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Alginatos/metabolismo , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Quitosana/metabolismo , Ácido Desoxicólico/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Insulina/metabolismo , Masculino , Nanopartículas/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Methods Mol Biol ; 2326: 267-271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097275

RESUMO

Cadmium (Cd) is widespread in the soil, water, and atmosphere, so Cd toxicity to human can happen by breathing in air, drinking water, and eating food from plant grown in Cd-contaminated soil. Cd pollution draws a lot of attention from the scientific community and also regulatory agents and is researched widely by using both plant and animal system. In this protocol, the detection of cadmium (Cd) is described in soil and mature maize (Zea mays) plant with the atomic absorption spectrometer. The Cd uptake, translocation factor, and Cd health risk index are also introduced. The protocol can be modified slightly to measure Cd in different types of plants.


Assuntos
Cádmio/análise , Poluentes do Solo/análise , Solo/química , Zea mays/química , Transporte Biológico , Cádmio/metabolismo , Cádmio/toxicidade , Poluentes do Solo/metabolismo , Poluentes do Solo/toxicidade , Espectrofotometria Atômica/métodos , Zea mays/metabolismo
7.
Gynecol Oncol ; 161(3): 779-786, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33888337

RESUMO

OBJECTIVE: Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a lethal malignancy and little treatment progress has been made for decades. We sought to map its genetic profiles, and identify whether SCNEC harbor mutations and potential targets for therapeutic interventions. METHODS: Primary tumor tissue and blood samples were obtained from 51 patients with SCNEC. The next-generation sequencing was carried out to detect mutations of 520 cancer-related genes, including the entire exon regions of 312 genes and the hotspot mutation regions of 208 genes. Quantitative multiplex PCR was performed for the detection of seven high-risk HPV types. RESULTS: Of the 51 detected patients, 92.16% were positive for HPV 18. Ninety-eight percent of cases harbored genetic alterations. Two cases were observed with hypermutated phenotype and determined as MSI-H/dMMR. Genetic mutations were clustering in RTK/RAS(42.86%), PI3K-AKT(38.78%), p53 pathway(22.45%) and MYC family(20.41%). Mutations in genes involved in the p53 pathway indicate a poorer prognosis (3-year OS, 33.5% vs 59.9%, p = 0.031). A total of seven patients harboring mutations in homogeneous recombination repair (HRR) genes were reported. In addition, IRS2 and SOX2 were amplified in 14.9% and 6.12% of SCNEC patients, respectively. CONCLUSIONS: SCNEC is specifically associated with HPV 18 infection. Its genetic alterations are characterized by a combined feature of high-risk HPV driven events and mutations observed in common neuroendocrine carcinoma. We identified several targetable mutated genes, including KRAS, PIK3CA, IRS2, SOX2, and HRR genes, indicating the potential efficacy of target therapies in these patients. MSI-H/dMMR individuals may benefit from checkpoint blockade therapies.


Assuntos
Carcinoma Neuroendócrino/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , China , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Adulto Jovem
8.
Biomed Res Int ; 2021: 6631533, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816622

RESUMO

Endometrial cancer (EC) is a common gynecological malignancy worldwide whose therapy mainly depends on chemotherapy. In past years, an increasing number of studies indicate that hollow MnO2 could serve as a nanoplatform in the drug delivery system. The Brucea javanica oil emulsion (BJOE) has been illustrated to play a vital role in cancers. However, knowledge about the combined effect of H-MnO2-PEG/BJOE in endometrial cancer remains ambiguous up to now. In the present work, we prepared a drug-delivery vector H-MnO2-PEG by chemical synthesis and found that H-MnO2-PEG significantly inhibited cell proliferation in endometrial cancer cells. Moreover, the combination of H-MnO2-PEG/BJOE could repress cell proliferation more efficiently and promote cell apoptosis. Mechanistically, we found that BJOE exerted its role as a promoter of endometrial apoptosis by regulating relative protein expressions. In general, the present study demonstrates that H-MnO2-PEG functions as a critical vector in the tumor microenvironment of endometrial cancer and the significant effect of H-MnO2-PEG/BJOE on cancer cells, suggesting a new paradigm for the treatment of endometrial cancer.


Assuntos
Apoptose/efeitos dos fármacos , Brucea/química , Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio , Compostos de Manganês , Óxidos , Óleos Vegetais , Linhagem Celular Tumoral , Emulsões , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Óxidos/química , Óxidos/farmacologia , Óleos Vegetais/química , Óleos Vegetais/farmacologia
9.
J Prosthet Dent ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33454114

RESUMO

STATEMENT OF PROBLEM: Screw- and cement-retained prostheses (SCRPs) may be contaminated during fabrication in a dental laboratory, leading to mechanical and biological complications related to the implant treatment. Studies that explored methods to efficiently and conveniently clean and disinfect SCRPs are sparse. PURPOSE: The purpose of this clinical study was to compare the efficiency of 3 methods to remove contaminants and microorganisms present on the surface of an SCRP. MATERIAL AND METHODS: Forty-eight 1-unit SCRPs fabricated in a dental laboratory were randomly divided into 3 groups: wiping, soaking, or ultrasonic cleaning. The presence of contaminants was determined by scanning electron microscopy, and microbial cells were cultured before and after treatment. Bacterial colony-forming units (CFUs) on the surface of the SCRPs and contamination density at the implant-abutment interface and emergence profile area were assessed. Statistical tests including ANCOVA were used to compare the efficiency of different methods before and after treatment (α=.05). RESULTS: Significant differences in contamination density were noted during the treatment at the implant-abutment interface and at the emergence profile area in the 3 groups (P<.05), but no significant differences were observed in the number of CFUs (P>.05). There were significant differences among the 3 methods for cleaning efficiency both at the implant-abutment interface (P=.023) and the emergence profile area (P=.038). At the implant-abutment interface, the contamination density after treatment was lower in the ultrasonic cleaning group than that in the soaking group (P=.007), whereas at the emergence profile area, the contamination density after treatment was lower in the ultrasonic cleaning group than that in the wiping group (P=.019) and the soaking group (P=.048). CONCLUSIONS: All 3 treatment methods reduced contaminants on the SCRP surface, but ultrasonic cleaning yielded the most favorable results. However, none of the methods provided additional disinfection for SCRPs previously disinfected by ozone and UV in a dental laboratory.

10.
Lancet Oncol ; 21(12): 1563-1573, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33284113

RESUMO

BACKGROUND: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. METHODS: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. FINDINGS: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. INTERPRETATION: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Axitinibe/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Sunitinibe/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Sunitinibe/efeitos adversos , Fatores de Tempo
11.
BMC Plant Biol ; 20(1): 501, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33143654

RESUMO

BACKGROUND: Nitrogen (N) deficiency is a major constraint for plant production in many areas. Developing the new crop genotypes with high productivity under N deficiency is an important approach to maintain agricultural production. Therefore, understanding how plant response to N deficiency and the mechanism of N-deficiency tolerance are very important for sustainable development of modern crop production. RESULTS: In this study, the physiological responses and fatty acid composition were investigated in 24 wheat cultivars under N-deficient stress. Through Pearson's correlation analysis and principal component analysis, the responses of 24 wheat cultivars were evaluated. The results showed that the plant growth and carbohydrate metabolism were all differently affected by N deficiency in all tested wheat cultivars. The seedlings that had high shoot biomass also maintained high level of chlorophyll content under N deficiency. Moreover, the changes in fatty acid composition, especially the linolenic acid (18:3) and the double bond index (DBI), showed close positive correlations with the shoot dry weight and chlorophyll content alterations in response to N-deficient condition. These results indicated that beside the chlorophyll content, the linolenic acid content and DBI may also contribute to N-deficiency adaptation, thus could be considered as efficient indicators for evaluation of different response in wheat seedlings under N-deficient condition. CONCLUSIONS: The alteration in fatty acid composition can potentially contribute to N-deficiency tolerance in plants, and the regulation of fatty acid compositions maybe an effective strategy for plants to adapt to N-deficient stress.


Assuntos
Nitrogênio/deficiência , Plântula/fisiologia , Triticum/fisiologia , Ácido alfa-Linoleico/fisiologia , Ácidos Graxos/metabolismo , Brotos de Planta/crescimento & desenvolvimento , Plântula/crescimento & desenvolvimento , Estresse Fisiológico , Triticum/crescimento & desenvolvimento , Ácido alfa-Linoleico/metabolismo
12.
Eur J Med Chem ; 206: 112494, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32890974

RESUMO

Ubiquitin-proteasome system, autophagy-lysosome pathway and N-end rule pathway are crucial protein quality control mechanisms in human body. Hijacking these endogenous protein degrading measures by chimera degraders could be a revolutionary strategy for the discovery of small-molecule drugs. As the most advanced chimera degraders, PROTACs have demonstrated the potential by delivering two drug candidates into clinical trials. The development of chimera degraders exploiting these three pathways are reviewed, a focus is given on the chemical structures and their influences on biological effects from a viewpoint of medicinal chemistry.


Assuntos
Descoberta de Drogas , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/química , Ubiquitina/química
13.
Ecotoxicol Environ Saf ; 203: 110999, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888604

RESUMO

Aluminium (Al) is a key element that plays a major role in inhibiting plant growth and productivity under acidic soils. While lipids may be involved in plant tolerance/sensitivity to Al, the role of monogalactosyldiacylglycerol (MGDG) in Al response remains unknown. In this study, Arabidopsis MGDG synthase (AtMGD) mutants (mgd1, mgd2 and mgd3) and wild-type (Col-0) plants were treated with AlCl3; the effect of aluminium on root growth, aluminium distribution, plasma membrane integrity, lipid peroxidation, hydrogen peroxide content and membrane lipid compositions were analysed. Under Al stress, mgd mutants exhibited a more severe root growth inhibition, plasma membrane integrity damage and lipid peroxidation compared to Col-0. Al accumulation in root tips showed no difference between Col-0 and mutants under Al stress. Lipid analysis demonstrated that under Al treatment the MGDG content in all plants and MGDG/DGDG (digalactosyldiacylglycerol) remarkably reduced, especially in mutants impairing the stability and permeability of the plasma membrane. These results indicate that the Arabidopsis mgd mutants are hypersensitive to Al stress due to the reduction in MGDG content, and this is of great significance in the discovery of effective measures for plants to inhibit aluminium toxicity.


Assuntos
Alumínio/toxicidade , Arabidopsis/efeitos dos fármacos , Galactolipídeos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poluentes do Solo/toxicidade , Alumínio/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Galactolipídeos/genética , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos de Membrana/metabolismo , Mutação , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Poluentes do Solo/metabolismo
14.
Int J Clin Oncol ; 25(12): 2144-2150, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32779039

RESUMO

PURPOSE: The purpose of this study was to elucidate our experience in the diagnosis and treatment of adenoid cystic carcinoma of the vulva (ACC-vulva) and to assess the clinicopathological characteristics and prognosis among ACC-vulva patients. METHODS: A retrospective study of seventeen patients was performed to illustrate the demographic information, clinical performance, pathological characteristics, treatment modality, and development of local recurrence or distant metastasis, as well as the survival outcome. RESULTS: The median age at diagnosis was 56 years (range, 26-71 years). Radical local excision was performed on fifteen patients, and two patient received radical hemi-vulvectomy. Six patients received ipsilateral inguinal lymphadenectomy. Involvement of the resection margin was observed in six patients. The postoperative pathologic diagnosis showed no proof of inguinal lymph node metastasis in all the six patients receiving lymphadenectomy. However, the perineural invasion was observed in all patients. Postoperative adjuvant radiotherapy was applied to five patients who had positive resection margin. The mean survival time except for that in four patients (recent case) was 47.8 months (range, 23-78 months). CONCLUSION: Radical resection towards negative margins seems to be acceptable as initial treatment. Adjuvant radiotherapy is a preferable treatment modality for patients with high-risk factors pathologically or patients with local recurrence.


Assuntos
Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/patologia , Neoplasias Vulvares/mortalidade , Neoplasias Vulvares/patologia , Adulto , Idoso , Carcinoma Adenoide Cístico/radioterapia , Carcinoma Adenoide Cístico/cirurgia , Feminino , Humanos , Excisão de Linfonodo/métodos , Linfonodos/patologia , Metástase Linfática/patologia , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias Vulvares/radioterapia , Neoplasias Vulvares/cirurgia
15.
Drug Deliv ; 27(1): 1147-1155, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32729341

RESUMO

Increasingly attention has been paid to the transdermal drug delivery systems with microneedles owing to their excellent compliance, high efficiency, and controllable drug release, therefore, become promising alternative with tremendous advantages for delivering specific drugs such as huperzine A (Hup A) for treatment of Alzheimer's disease (AD) yet with low oral bioavailability. The purpose of the present study is to design, prepare, and evaluate a dissolving microneedle patch (DMNP) as a transdermal delivery system for the Hup A, investigating its in vitro drug release profiles and in vivo pharmacokinetics as well as pharmacodynamics treating of AD. Skin penetration experiments and intradermal dissolution tests showed that the blank DMNP could successfully penetrate the skin with an adequate depth and could be quickly dissolved within 5 min. In vitro transdermal release tests exhibited that more than 80% of the Hup A was accumulatively permeated from DMNP through the skin within three days, indicating a sustained release profile. In vivo pharmacokinetic analysis demonstrated that the DMNP group resulted in longer T max (twofold), longer t 1/2 (fivefold), lower C max (3:4), and larger AUC(0-∞) (twofold), compared with the oral group at the same dose of Hup A. Pharmacodynamic research showed a significant improvement in cognitive function in AD rats treated with DMNP-Hup A and Oral-Hup A, as compared to the model group without treatment. Those results demonstrated that this predesigned DMNP is a promising alternative to deliver Hup A transdermally for the treatment of AD.


Assuntos
Alcaloides/administração & dosagem , Alcaloides/farmacologia , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Microinjeções/métodos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacologia , Administração Cutânea , Alcaloides/farmacocinética , Animais , Área Sob a Curva , Materiais Biocompatíveis , Inibidores da Colinesterase/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Meia-Vida , Masculino , Agulhas , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/farmacocinética , Pele/metabolismo
16.
BMC Plant Biol ; 20(1): 218, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410579

RESUMO

BACKGROUND: Water deficiency is likely to become more frequent and intense as a result of global climate change, which may severely impact agricultural production in the world. The positive effects of melatonin (MEL) on alleviation drought or osmotic stress-induced water deficiency in plants has been well reported. However, the underlying mechanism of MEL on the detailed process of plant water uptake and transport under water deficiency condition remains largely unknown. RESULTS: Application of 1 µM MEL led to enhanced tolerance to water deficiency stress in maize seedlings, as evidenced by maintaining the higher photosynthetic parameters, leaf water status and plant transpiration rate. The relatively higher whole-plant hydraulic conductance (Kplant) and root hydraulic conductance (Lpr) in MEL-treated seedlings suggest that exogenous MEL alleviated water deficiency stress by promoting root water absorption. HgCl2 (aquaporin inhibitor) treatment inhibit the transpiration rate in MEL-treated plants greater than those of MEL-untreated; after recovery by dithiothreitol (DTT, anti-inhibitor), the transpiration rate in MEL-treated plants increased much higher than those of untreated plants. Moreover, under water deficiency, the transcription level of aquaporin genes was up-regulated by MEL application, and the H2O2 was less accumulated in MEL-treated root. CONCLUSIONS: Exogenous MEL promoted aquaporin activity, which contributed to the maintaining of Lpr and Kplant under short-term water deficiency. The increased water uptake and transport lead to improved water status and thus increased tolerance to PEG-induced short-term water deficiency in maize seedlings.


Assuntos
Melatonina/farmacologia , Transpiração Vegetal , Polietilenoglicóis/administração & dosagem , Água/metabolismo , Zea mays/fisiologia , Zea mays/efeitos dos fármacos
17.
J Hazard Mater ; 395: 122679, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32330780

RESUMO

Cadmium (Cd) contamination is a serious threat to plants and humans. Application of silicon (Si) or nitric oxide (NO) could alleviate Cd accumulation and toxicity in plants, but whether they have joint effects on alleviating of Cd accumulation and toxicity are not known. Therefore, the combined effect of Si and NO application on maize growth, Cd uptake, Cd transports and Cd accumulation were investigated in a pot experiment. Here, we reported that Cd stress decreased growth, caused Cd accumulation in plants. The combined application of Si and NO triggered a significant response in maize, increasing plant growth and reducing Cd uptake, accumulation, translocation and bioaccumulation factors under Cd stress. The grain Cd concentration was decreased by 66 % in the Si and NO combined treatment than Cd treatment. Moreover, the combined application of Si and NO reduced Cd health risk index in maize more effectively than either treatment alone. This study provided new evidence that Si and NO have a strong joint effect on alleviating the adverse effects of Cd toxicity by decreasing Cd uptake and accumulation. We advocate for supplement of Cd-contaminated soil with Si fertilizers and treatment of crops with NO as a practical approach to alleviating Cd toxicity.


Assuntos
Cádmio , Poluentes do Solo , Cádmio/análise , Cádmio/toxicidade , Humanos , Óxido Nítrico , Silício , Poluentes do Solo/análise , Poluentes do Solo/toxicidade , Zea mays
18.
Drug Dev Ind Pharm ; 46(1): 57-69, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31813288

RESUMO

Liver fibrosis is a major pathological feature of chronic liver diseases, and effective therapies are limited at present. Asiatic acid (AA) is a triterpenoid isolated from Centella asiatica, which exhibits efficient anti-inflammatory and anti-oxidative activities. However, AA shows very low plasma levels after oral administration. In this study, AA loading PEGylated nanostructured lipid carriers (P-AA-NLCs) were prepared. P-AA-NLCs were characterized for particle size distribution, polydispersity index, entrapment efficiency, X-ray powder diffraction (XRD) pattern, differential scanning colorimeter (DSC), and transmission electron microscopy (TEM). The intestinal absorption, in vivo distribution, pharmacokinetics, and anti-fibrosis effects of P-AA-NLC were studied compared with that of AA-NLC. In situ single-pass intestinal perfusion model shows that there are significant differences in absorption between the free and NLCs formulation. The Peff values of P-AA-NLC were significantly enhanced in all four intestinal segments compared to AA-NLC and free AA (p < .05). fa% and Ka showed similar trends, suggesting the PEGylated NLC can improve the gastrointestinal absorption of the drug. The pharmacokinetic studies presented that P-AA-NLC prolonged blood circulation times with a 1.5-fold higher relative bioavailability compared with AA-NLC. In vivo distribution experiments demonstrated that the fluorescence concentration in the liver was higher than that in other organs and the fluorescence intensity in the liver of DIR-P-NLC was about 1.3 times that of DIR-NLC. In addition, oral administration of P-AA-NLC can significantly attenuate CCl4-induced liver fibrosis and functional impairment in a dosage-dependent manner, including an increase in the albumin (ALB) and decrease in aspartate aminotransferase (AST) and alanine transaminase (ALT). Moreover, the MDA and HYP in liver tissue were downregulated, while the SOD activity was upregulated. In conclusion, P-AA-NLC can increase gastrointestinal absorption of AA and enhance anti-liver fibrosis effects in SD rats.


Assuntos
Lipídeos/química , Cirrose Hepática/prevenção & controle , Nanoestruturas , Triterpenos Pentacíclicos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Centella/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Absorção Intestinal , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tamanho da Partícula , Triterpenos Pentacíclicos/farmacocinética , Triterpenos Pentacíclicos/farmacologia , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley
19.
Ying Yong Sheng Tai Xue Bao ; 30(11): 3777-3786, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31833691

RESUMO

The compensation effect of re-watering after drought has been widely reported in various crops during different growth stages. It is considered as an important self-regulation mechanism for plants to resist abiotic stresses and also an efficient utilization of limited water resource. In this study, two rounds of re-watering after drought treatments were carried out during tuber expansion period of potato, to investigate the drought threshold of potato and explore the potential mechanisms of compensation effect with source-sink aspect. We used virus-free plantlets of "Atlantic" potato as experimental materials. Four treatments were included: sufficient water supply (W), re-watering after mild drought (D1-W), re-watering after medium drought (D2-W) and re-watering after severe drought (D3-W). The results showed that potato yield exhibited an over-compensation effect after two rounds of D1-W treatment, with water use efficiency and yield being increased by 17.5% and 6.3%, respectively, compared with the sufficient water supply. D2-W treatment had no significant effect on potato yield, but water use efficiency was increased by 8.4%, indicating a near-equivalent compensation effect. On the contrary, D3-W treatment did not show any compensation effect in yield. In addition, leaf chlorophyll content, net photosynthetic rate, and leaf area were all reduced after drought treatment, indicating a reduction in "source" size and activity. After re-watering, D1-W and D2-W treatments showed over-compensation and compensation effects through improving source supply capacity. Meanwhile, re-watering after moderate drought increased the sink activity through significantly enhancing the activities of key enzymes in tubers (sink), thus increased the average weight of tubers. In conclusion, re-watering after moderate drought stress during potato tuber expansion period had compensation and over-compensation effects on both source and sink, and thus could compensate for the drought-induced yield loss and improve water use efficiency.


Assuntos
Solanum tuberosum , Secas , Fotossíntese , Tubérculos , Água
20.
Drug Deliv ; 26(1): 1235-1242, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752553

RESUMO

Objective: To prepare everolimus nanoformulations and increase their solubility to suit their application in the eye. Methods: The everolimus micelles was prepared by thin film dispersion method using Tween-80 (P80) and polyoxyethylene stearate (P40S) as carriers. In addition, the everolimus nanosuspension was prepared by injection method using poloxamer 407 (P407), hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) as stabilizers. It was characterized in terms of particle size, PDI and encapsulation efficiency or drug loading. The in vitro release and in vitro rabbit scleral permeability characteristics were investigated, and the pharmacokinetics of anterior chamber drug in rabbit eyes were studied. Results: The average particle size of the micelles was (8.74 ± 0.21) nm, the encapsulation efficiency and drug loading were (90.12 ± 1.18)% and (2.14 ± 0.028)%, while the average particle size of the nanosuspension was (156.47 ± 1.10) nm, and the drug loading was (16.51 ± 0.21)%, respectively. Both in vitro release and rabbit scleral permeation models were consistent with the Higuchi equation. The pharmacokinetic experiments of aqueous humor showed that area under the curve of everolimus nanosuspension was about 3 times higher than that of micelles. Micelles could be achieved in the eye and maintained for a long time. Conclusion: The preparation of everolimus micelles or nanosuspension for eye are suitable for ocular administration and expected to be new dosage form for corneal transplantation immunological rejection or other ocular disease.


Assuntos
Córnea/efeitos dos fármacos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Nanopartículas/química , Esclera/efeitos dos fármacos , Administração Oftálmica , Animais , Córnea/metabolismo , Liberação Controlada de Fármacos , Everolimo/farmacocinética , Imunossupressores/farmacocinética , Micelas , Tamanho da Partícula , Permeabilidade , Coelhos , Esclera/metabolismo
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