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1.
Nature ; 586(7830): 572-577, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32726802

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.


Asunto(s)
Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/inmunología , Neumonía Viral/prevención & control , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , COVID-19 , Vacunas contra la COVID-19 , Humanos , Macaca mulatta/inmunología , Macaca mulatta/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Animales , Modelos Moleculares , Dominios Proteicos , SARS-CoV-2 , Suero/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T/inmunología , Vacunación
2.
Cell Mol Life Sci ; 81(1): 92, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38363375

RESUMEN

The maintenance of genome integrity in the germline is crucial for mammalian development. Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element that makes up about 17% of the human genome and poses a threat to genome integrity. N6-methyl-adenosine (m6A) plays an essential role in regulating various biological processes. However, the function of m6A modification in L1 retrotransposons and human germline development remains largely unknown. Here we knocked out the m6A methyltransferase METTL3 or the m6A reader YTHDF2 in human embryonic stem cells (hESCs) and discovered that METTL3 and YTHDF2 are crucial for inducing human spermatogonial stem cells (hSSCs) from hESCs in vitro. The removal of METTL3 or YTHDF2 resulted in increased L1 retrotransposition and reduced the efficiency of SSC differentiation in vitro. Further analysis showed that YTHDF2 recognizes the METTL3-catalyzed m6A modification of L1 retrotransposons and degrades L1 mRNA through autophagy, thereby blocking L1 retrotransposition. Moreover, the study confirmed that m6A modification in human fetal germ cells promotes the degradation of L1 retrotransposon RNA, preventing the insertion of new L1 retrotransposons into the genome. Interestingly, L1 retrotransposon RNA was highly expressed while METTL3 was significantly downregulated in the seminal plasma of azoospermic patients with meiotic arrest compared to males with normal fertility. Additionally, we identified some potentially pathogenic variants in m6A-related genes in azoospermic men with meiotic arrest. In summary, our study suggests that m6A modification serves as a guardian of genome stability during human germline development and provides novel insights into the function and regulatory mechanisms of m6A modification in restricting L1 retrotransposition.


Asunto(s)
Azoospermia , Retroelementos , Masculino , Animales , Humanos , Retroelementos/genética , ARN , Azoospermia/genética , Diferenciación Celular/genética , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN Mensajero/genética , Mamíferos/metabolismo
3.
Vet Ophthalmol ; 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38413368

RESUMEN

OBJECTIVE: This study documented the application of porcine small intestinal submucosa (SIS) as a stand-alone scaffold for treating deep corneal defects in cats. METHODS: Medical records of 20 cats with deep stromal ulcers, perforations, or corneal sequestra that underwent surgical treatment with SIS grafts between 2021 and 2022 were retrospectively reviewed. Data on re-epithelialization time, corneal transparency score, and complications were collected to analyze the reconstruction of deep corneal defects after SIS biomaterial implantation. RESULTS: All cats were unilaterally affected. The corneal defects varied in size, with a median diameter of 8.3 mm (range: 3-15 mm). Re-epithelialization of the SIS graft was completed 16-32 days after surgery (median, 22.3 days). No, mild, or moderate corneal transparency was detected in 90% of the cases. Complications were observed in eight cases (40%), including aqueous leakage (10%), partial SIS malacia (25%), and persistent bullous keratopathy (5%). The follow-up period ranged 90-725 days, with a median duration of 255 days. The SIS graft was successfully applied as a single scaffold in 17 of 20 cases (85%). CONCLUSION: The results of this study suggest that the application of commercial SIS is an effective surgical technique for managing deep corneal defects in cats.

4.
Chemistry ; 29(16): e202203142, 2023 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-36565275

RESUMEN

Enhancing catalytic performance as well as reducing catalyst cost are the eternal pursuit for the catalysis community. Herein, a simple and effective palladium-doped cobalt (Pd/Co) catalyst with high Pd atom utilization efficiency was synthesized via galvanic replacement reaction for the selective hydrogenation of nitrobenzene with H2 at room temperature, delivering >99 % yield of aniline with up to 158 times higher catalytic activity than commercial palladium powder. Detailed characterizations and DFT calculations revealed that Co-Pd interaction leads to a decrease in electron density of Pd and the distance between Pd atoms that results in the enhanced catalytic performance. Further experiments indicated that the Pd/Co catalyst serves as a highly efficient, selective, and recyclable catalyst for a range of nitroarene substrates. This work might provide a green and sustainable methodology to design and synthesize highly active catalysts with high utilization efficiency of the noble metals in fundamental and applied research.

5.
Environ Res ; 216(Pt 2): 114601, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36265601

RESUMEN

Bisphenol A (BPA), one of the widely known endocrine-disrupting chemicals, can be effectively degraded by advanced oxidation processes in water because of the powerful reactive oxygen species. In this study, Fenton, UV/Fenton, and metal ion/peroxymonosulfate (PMS) processes were compared to investigate BPA degradation efficiency and pathways initiated by hydroxyl radicals and sulfate radicals. In contrast to the Fenton system, which only degraded 60% of BPA within 15 min, the UV/Fenton system could degrade greater than 80% of BPA, because more hydroxyl radicals (•OH) were generated under the reduction of Fe3+ to Fe2+. The optimized parameters of the UV/Fenton system were as follows: 8 µmol/L of Fe2+, 80 µmol/L of H2O2, and a pH value of 3.0. As for the metal ion/PMS system, the BPA degradation efficiency was closely associated with the applied metal ions, and the order was as follows: Co2+/PMS (∼100%) > Fe2+/PMS (∼80%) > Cu2+/PMS (∼79%). The degradation pathways of BPA were theoretically interpreted through density functional theory prediction and degradation products during various processes. Two major initial reaction sites (4C and 6C) for •OH initiated using the UV/Fenton system and one initial reaction site (4C) for sulfate radicals (SO4•-) using the metal ion/PMS system were recognized for BPA degradation processes. The degradation products by •OH showed a larger average molecular weight than those by SO4•-. These studies are instructive for the application of different advanced oxidation systems in the treatment process of BPA in wastewater.


Asunto(s)
Radical Hidroxilo , Contaminantes Químicos del Agua , Peróxido de Hidrógeno/química , Agua , Compuestos de Bencidrilo , Sulfatos/química , Oxidación-Reducción , Contaminantes Químicos del Agua/análisis
6.
BMC Med ; 20(1): 411, 2022 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-36303207

RESUMEN

BACKGROUND: The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. METHODS: Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). RESULTS: PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the "immune-cold" environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. CONCLUSIONS: Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.


Asunto(s)
Neoplasias de la Mama , Nanopartículas Multifuncionales , Nanopartículas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Adyuvantes Inmunológicos , Línea Celular Tumoral , Inmunoterapia , Autofagia , Cloroquina/farmacología , Nanopartículas/uso terapéutico
8.
Int J Mol Sci ; 23(18)2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36142765

RESUMEN

Much progress has been made in determining that paternal environmental exposures can remodel their spermatozoa small noncoding RNAs (sncRANs) and, in turn, affect the phenotypes of their offspring. Studies have shown that changes in the spermatozoa sncRNAs profile occur during passing through the epididymis. Due to the absence of transcription and translation in the epididymis, spermatozoa remodel their sncRNAs profile through communication with the epididymal microenvironment. Since epididymosomes contribute to the process of spermatozoa maturation by mediating the crosstalk between the epididymis and the passing spermatozoa, they are considered to be the leading candidate to mediate these changes. Previous studies and reviews on the role of epididymal transfer proteins in sperm maturation and function are myriad. This review focuses on the role and mechanisms of epididymosome-mediated transfer of sncRNAs cargoes onembryonic development and offspring health.


Asunto(s)
ARN Pequeño no Traducido , Animales , Desarrollo Embrionario , Epidídimo/metabolismo , Masculino , ARN Pequeño no Traducido/genética , Semen , Maduración del Esperma , Espermatozoides/metabolismo
9.
Mol Cancer ; 20(1): 33, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33593376

RESUMEN

mRNA vaccines have tremendous potential to fight against cancer and viral diseases due to superiorities in safety, efficacy and industrial production. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. Based on the immunological study, mRNA vaccines are coupled with immunologic adjuvant and various delivery strategies. Except for sequence optimization, the assistance of mRNA-delivering strategies is another method to stabilize mRNAs and improve their efficacy. The understanding of increasing the antigen reactiveness gains insight into mRNA-induced innate immunity and adaptive immunity without antibody-dependent enhancement activity. Therefore, to address the problem, scientists further exploited carrier-based mRNA vaccines (lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particle and cationic nanoemulsion), naked mRNA vaccines and dendritic cells-based mRNA vaccines. The article will discuss the molecular biology of mRNA vaccines and underlying anti-virus and anti-tumor mechanisms, with an introduction of their immunological phenomena, delivery strategies, their importance on Corona Virus Disease 2019 (COVID-19) and related clinical trials against cancer and viral diseases. Finally, we will discuss the challenge of mRNA vaccines against bacterial and parasitic diseases.


Asunto(s)
Vacunas Sintéticas/uso terapéutico , Animales , COVID-19/inmunología , Técnicas de Transferencia de Gen , Humanos , Inmunidad Humoral , Inmunoterapia , Estabilidad del ARN , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Vacunas de ARNm
10.
Plant Mol Biol ; 104(1-2): 67-79, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32621165

RESUMEN

Acetylation and deacetylation of histones are important for regulating a series of biological processes in plants. Histone deacetylases (HDACs) control the histone deacetylation that plays an important role in plant response to abiotic stress. In our study, we show the evidence that GhHDT4D (a member of the HD2 subfamily of HDACs) is involved in cotton (Gossypium hirsutum) response to drought stress. Overexpression of GhHDT4D in Arabidopsis increased plant tolerance to drought, whereas silencing GhHDT4D in cotton resulted in plant sensitivity to drought. Simultaneously, the H3K9 acetylation level was altered in the GhHDT4D silenced cotton, compared with the controls. Further study revealed that GhHDT4D suppressed the transcription of GhWRKY33, which plays a negative role in cotton defense to drought, by reducing its H3K9 acetylation level. The expressions of the stress-related genes, such as GhDREB2A, GhDREB2C, GhSOS2, GhRD20-1, GhRD20-2 and GhRD29A, were significantly decreased in the GhHDT4D silenced cotton, but increased in the GhWRKY33 silenced cotton. Given these data together, our findings suggested that GhHDT4D may enhance drought tolerance by suppressing the expression of GhWRKY33, thereby activating the downstream drought response genes in cotton.


Asunto(s)
Sequías , Gossypium/metabolismo , Histona Desacetilasas/metabolismo , Estrés Fisiológico/fisiología , Acetilación , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Silenciador del Gen , Gossypium/genética , Histona Desacetilasas/genética , Histonas/genética , Histonas/metabolismo , Filogenia , Plantas Modificadas Genéticamente , Regiones Promotoras Genéticas , Estrés Fisiológico/genética , Transcriptoma
11.
Mol Cancer ; 19(1): 136, 2020 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-32887628

RESUMEN

The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.


Asunto(s)
Carcinogénesis/genética , Proteínas de la Membrana/genética , Neoplasias/genética , Nucleotidiltransferasas/genética , Terapia Biológica/tendencias , Carcinogénesis/inmunología , Humanos , Inmunoterapia/tendencias , Interferón Tipo I/genética , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Transducción de Señal/genética , Xantinas/uso terapéutico
12.
BMC Plant Biol ; 20(1): 217, 2020 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-32410659

RESUMEN

BACKGROUND: Mitogen-activated protein kinase kinase kinases (MAPKKKs) are significant components in the MAPK signal pathway and play essential roles in regulating plants against drought stress. To explore MAPKKK gene family functioning in cotton response and resistance to drought stress, we conducted a systematic analysis of GhMAPKKKs. RESULTS: In this study, 157 nonredundant GhMAPKKKs (including 87 RAFs, 46 MEKKs and 24 ZIKs) were identified in cotton (Gossypium hirsutum). These GhMAPKKK genes are unevenly distributed on 26 chromosomes, and segmental duplication is the major way for the enlargement of MAPKKK family. Furthermore, members within the same subfamily share a similar gene structure and motif composition. A lot of cis-elements relevant to plant growth and response to stresses are distributed in promoter regions of GhMAPKKKs. Additionally, these GhMAPKKKs show differential expression patterns in cotton tissues. The transcription levels of most genes were markedly altered in cotton under heat, cold and PEG treatments, while the expressions of some GhMAPKKKs were induced in cotton under drought stress. Among these drought-induced genes, we selected GhRAF4 and GhMEKK12 for further functional characterization by virus-induced gene silencing (VIGS) method. The experimental results indicated that the gene-silenced cotton displayed decreased tolerance to drought stress. Malondialdehyde (MDA) content was higher, but proline accumulation, relative leaf water content and activities of superoxide dismutase (SOD) and peroxidase (POD) were lower in the gene-silenced cotton, compared with those in the controls, under drought stress. CONCLUSION: Collectively, a systematic survey of gene structure, chromosomal location, motif composition and evolutionary relationship of MAPKKKs were performed in upland cotton (Gossypium hirsutum). The following expression and functional study showed that some of them take important parts in cotton drought tolerance. Thus, the data presented here may provide a foundation for further investigating the roles of GhMAPKKKs in cotton response and resistance to drought stress.


Asunto(s)
Sequías , Regulación de la Expresión Génica de las Plantas , Gossypium/fisiología , Quinasas Quinasa Quinasa PAM/genética , Familia de Multigenes , Proteínas de Plantas/genética , Gossypium/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas de Plantas/metabolismo , Estrés Fisiológico/genética
14.
Drug Dev Ind Pharm ; 45(1): 96-104, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30196732

RESUMEN

OBJECTIVE: This article aims to design low molecular weight chitosan (LMWC)-based conjugates of Rhein (RH) by means of an amino acid linker (Alanine) for improved solubility and enhanced bioavailability. SIGNIFICANCE: Rhein is a potential candidate for the therapy of kidney disease. However, the poor solubility, inadequate bioavailability, and lack of proper formulation restrict its clinical applicability. LMWC-drug conjugates offer the potential to improve the water-solubility of RH, increase its oral absorption, and thereby enhance its bioavailability. METHODS: The conjugates were synthesized via a carbodiimide reaction and confirmed using UV-vis, FTIR, and 1H-NMR spectroscopy. The water-solubility and in vitro release properties were evaluated. Free RH and RH-LMWC conjugates were administered at an equivalent oral gavage dose of RH at 35 mg/kg for pharmacokinetic studies in Sprague Dawley rats. RESULTS: The conjugates with RH content of 9.65% were successfully synthesized and featured a satisfactory water-solubility of 9.73 mg/mL, which exhibited a sustained release pattern over 72 h, and the enzymes present may promote the degradation of the conjugate to increase the release of Rhein. Oral administration of RH-LMWC conjugates to rats led to seven-folds and 3.1-folds increase in the T1/2 and AUC0-∞, respectively, as compared to RH suspension. CONCLUSION: The present work demonstrated that the RH-LMWC conjugates exhibited sustained release properties with outstanding oral bioavailability enhancements compared to administration of RH itself. Potentially, RH-LMWC conjugates may serve as a promising lead for developing a new platform for RH oral delivery.


Asunto(s)
Antraquinonas/síntesis química , Antraquinonas/farmacocinética , Quitosano/síntesis química , Quitosano/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Administración Oral , Animales , Antraquinonas/administración & dosificación , Disponibilidad Biológica , Quitosano/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Masculino , Peso Molecular , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento
15.
Zhongguo Zhong Yao Za Zhi ; 44(4): 758-764, 2019 Feb.
Artículo en Zh | MEDLINE | ID: mdl-30989889

RESUMEN

The aim of this paper was to investigate the effect of emodin on gut microbiota in acute kidney injury rats( AKI). Rats were randomly divided into several groups: normal group,model group,low-dose of emodin group( 10 mg·kg~(-1)),medium-dose of emodin group( 25 mg·kg~(-1)),high-dose of emodin group( 50 mg·kg~(-1)) and control group( 5 mg·kg~(-1) of benazepril hydrochloride).The AKI model rats were established by intraperitoneal injection of small dose of gentamicin sulfate for 7 days. Two hours after intraperitoneal injection,except for the normal group and the model group,the other groups were given corresponding doses of drugs for 15 days. The serum levels of serum creatinine( SCr),urea nitrogen( BUN),plasma endotoxin level,24 h urinary protein and D-lactate in the plasma were determined by sarcosine oxidase,urease method,tal reagent method,bromo cresol chloroform method and double antibody sandwich enzyme-linked immunoadsorbent assay,respectively. Gut microbial communities were assayed by fluorescent quantitative PCR methods. HE staining was used to detect the pathological changes of the kidneys. Compared with the normal group,there were significant differences in body weight,urinary protein( UTP),bacterial endotoxin,urea nitrogen,creatinine,D-lactate in the plasma and four bacterial contents in the model group( P<0. 05). The urinary protein,urea nitrogen,D-lactate,creatinine and plasma bacterial endotoxin in control group and each emodin group were lower than those in model group,especially for high-dose of emodin( P<0. 01). Moreover,pathology resolution in high-dose emodin was better than other groups. Except for low-dose of emodin group,qRT-PCR data suggested that the amounts of Escherichia coli and Enterococcus in medication administration group were increased,while the amounts of Lactobacilli and Bifidobacterium were reduced compared with model group( P<0. 05),especially for high-dose of emodin( P<0. 01). There is a clear imbalance of gut microbiota in rats with AKI. Emodin could regulate the imbalance of gut microbiota,which might be one of the mechanisms of its effects on AKI rats.


Asunto(s)
Lesión Renal Aguda , Microbioma Gastrointestinal , Animales , Nitrógeno de la Urea Sanguínea , Emodina , Riñón , Ratas , Ratas Sprague-Dawley
16.
Drug Dev Ind Pharm ; 43(11): 1885-1891, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28692315

RESUMEN

The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6 ± 5.95 nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71 ± 3.02%, and the drug loading was 1.56 ± 0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUCkidney/AUCplasma = 0.586 ± 0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.


Asunto(s)
Antraquinonas/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Riñón/metabolismo , Nanopartículas/química , Animales , Antraquinonas/química , Antraquinonas/metabolismo , Disponibilidad Biológica , Riñón/química , Nanopartículas/administración & dosificación , Ratas
17.
Mol Pharm ; 12(1): 274-86, 2015 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-25469833

RESUMEN

Multidrug resistance has remained a major cause of treatment failure in chemotherapy due to the presence of P-glycoproteins (P-gp) that actively pump drugs from inside the cell to the outside. P-gp inhibitors were developed and coadministered with chemotherapeutic drugs to overcome the effect of efflux pumps thus enhancing the chemosensitivity of therapeutics. Our study aimed at developing a lipid nanoemulsion system for the coencapsulation of doxorubicin (DOX) and bromotetrandrine (W198) to reverse multidrug resistance (MDR) in breast cancer. W198 was a potent P-gp inhibitor, and DOX was selected as a model compound which is a common substrate for P-gp. Coencapsulated DOX and W198 lipid nanoemulsions (DOX/W198-LNs) displayed significantly enhanced cytotoxicity in DOX-resistant human breast cancer cells (MCF-7/ADR) compared with DOX loaded lipid nanoemulsions (DOX-LNs) (p < 0.05), which is due to the enhanced intracellular uptake of DOX in MCF-7/ADR cells. The biodistribution study was performed using a nude mice xenograft model, which demonstrates enhanced tumor uptake of DOX in the DOX/W198-LN treated group. Compared with DOX solution, DOX/W198-LNs showed reduced cardiac toxicity and gastrointestinal injury in rats. Taken together, DOX/W198-LNs represent a promising formulation for overcoming MDR in breast cancer.


Asunto(s)
Antineoplásicos/química , Bencilisoquinolinas/química , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/química , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Animales , Apoptosis , Línea Celular Tumoral , Emulsiones , Femenino , Humanos , Lípidos/química , Ratones , Ratones Desnudos , Nanomedicina/métodos , Necrosis , Trasplante de Neoplasias , Ratas , Ratas Wistar , Distribución Tisular
18.
BMC Vet Res ; 11: 86, 2015 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-25880747

RESUMEN

BACKGROUND: Corticosterone is one of the most crucial glucocorticoids (GCs) in poultry. Our previous study shows that corticosterone can retard the longitudinal growth of bones by depressing the proliferation and differentiation of chondrocytes in broilers. The present study was designed to investigate whether corticosterone affect the development of chondrocytes and the synthesis of collagen in vitro. The chondrocytes were isolated from proximal tibial growth plates of 6-week-old broiler chickens and cultured with different doses of corticosterone for 48 h. Then the cell viability, alkaline phosphatase (ALP) activity and the expression of parathyroid hormone-related peptide (PTHrP) and type X collagen (Col X) were detected. RESULTS: At 10(-9)-10(-6) M concentration, corticosterone significantly inhibited the viability and differentiation of chondrocytes, as indicated by decreases in ALP and type X collagen expression. Conversely, there was completely opposite effect at 10(-10) M. In addition, the expression of PTHrP was significantly downregulated at 10(-6) M and 10(-8) M, and was upregulated at 10(-10) M. CONCLUSIONS: The results suggested that corticosterone regulated chicken chondrocytes performance depending on its concentration with high concentrations inhibiting the viability and differentiation of chondrocytes and light concentrations promoting them, and these roles of corticosterone may be in part mediated through PTHrP.


Asunto(s)
Pollos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Corticosterona/farmacología , Metabolismo Energético/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Relacionada con la Hormona Paratiroidea/genética , Proteína Relacionada con la Hormona Paratiroidea/metabolismo
19.
J Clin Anesth ; 92: 111301, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37865021

RESUMEN

STUDY OBJECTIVE: The incidence of pruritus from neuraxial opioids is about 60%. Pruritus causes discomfort and decreases the quality of recovery. This randomized double-blinded clinical trial was aimed to evaluate the prophylactic effects of a single dose IV nalmefene on the incidence and severity of epidural opioid-induced pruritus within 24 h after surgeries. DESIGN: A two-center, randomized, double blinded, controlled clinical trial. SETTING: The study was conducted from March 2022 to February 2023 at two tertiary care hospitals in China. PATIENTS: Patients aged between 18 and 80 years-old who underwent elective surgeries and received epidural analgesia intra- and post-operatively were screened for study enrollment. A total of 306 patients were enrolled, 302 patients underwent randomization and 296 patients were included in the final analysis. INTERVENTIONS: The nalmefene group was prophylactically given 0.5 µg/kg nalmefene intravenously while the control group was given the same volume of saline. MEASUREMENTS: The primary endpoint was the incidence of pruritus within 24 h after surgeries. The secondary endpoints included time of the first patient-reported pruritus, severity of pruritus after surgeries, severity of acute pain scores after surgeries and other anesthesia/analgesia related side effects. MAIN RESULTS: Pruritus occurred in 51 of the 147 (34.69%) patients in the control group and 35 of the 149 (23.49%) patients in the nalmefene group (odds ratio, 0.58; 95% CI, 0.35 to 0.96; P = 0.034) within 24 h postoperatively. Nalmefene group demonstrated delayed onset of pruritus, reduced severity of pruritus and decreased vomiting within 24 h after surgery. There were no significant differences in postoperative analgesia and the incidence of other anesthesia/analgesia associated side effects. CONCLUSIONS: A single dose of 0.5 µg/kg nalmefene intravenously significantly reduced the incidence and severity of epidural-opioid induced pruritus within 24 h after surgery without affecting the efficacy of epidural analgesia. TRIAL REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn) and the registration number is ChiCTR2100050463. Registered on August 27th, 2021.


Asunto(s)
Analgesia Epidural , Analgésicos Opioides , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Morfina , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Prurito/inducido químicamente , Prurito/epidemiología , Prurito/prevención & control , Analgesia Epidural/efectos adversos , Método Doble Ciego
20.
Biomimetics (Basel) ; 8(4)2023 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-37622976

RESUMEN

Dynamic objects bring about a large number of error accumulations in pose estimation of mobile robots in dynamic scenes, and result in the failure to build a map that is consistent with the surrounding environment. Along these lines, this paper presents a robust semi-direct 3D simultaneous localization and mapping (SLAM) algorithm for mobile robots based on dense optical flow. First, a preliminary estimation of the robot's pose is conducted using the sparse direct method and the homography matrix is utilized to compensate for the current frame image to reduce the image deformation caused by rotation during the robot's motion. Then, by calculating the dense optical flow field of two adjacent frames and segmenting the dynamic region in the scene based on the dynamic threshold, the local map points projected within the dynamic regions are eliminated. On this basis, the robot's pose is optimized by minimizing the reprojection error. Moreover, a high-performance keyframe selection strategy is developed, and keyframes are inserted when the robot's pose is successfully tracked. Meanwhile, feature points are extracted and matched to the keyframes for subsequent optimization and mapping. Considering that the direct method is subject to tracking failure in practical application scenarios, the feature points and map points of keyframes are employed in robot relocation. Finally, all keyframes and map points are used as optimization variables for global bundle adjustment (BA) optimization, so as to construct a globally consistent 3D dense octree map. A series of simulations and experiments demonstrate the superior performance of the proposed algorithm.

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