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1.
J Control Release ; 324: 228-237, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32413454

RESUMO

Poly(L-glutamic acid)-co-poly(ethylene glycol) block copolymers (PLE-PEG) are here investigated as polymers for conjugation to therapeutic proteins such as granulocyte colony stimulating factor (G-CSF) and human growth hormone (hGH). PLE-PEG block copolymers are able to stabilize and protect proteins from degradation and to prolong their residence time in the blood stream, features that are made possible thanks to PEG's intrinsic properties and the simultaneous presence of the biodegradable anionic PLE moiety. When PLE-PEG copolymers are selectively tethered to the N-terminus of G-CSF and hGH, they yield homogeneous monoconjugates that preserve the protein's secondary structure. During the current study the pharmacokinetics of PLE10-PEG20k-G-CSF and PLE20-PEG20k-G-CSF derivatives and their ability to induce granulopoiesis were, respectively, assessed in Sprague-Dawley rats and in C57BL6 mice. Our results show that the bioavailability and bioactivity of the derivatives are comparable to or better than those of PEG20k-Nter-G-CSF (commercially known as Pegfilgrastim). The therapeutic effects of PLE10-PEG20k-hGH and PLE20-PEG20k-hGH derivatives tested in hypophysectomized rats demonstrate that the presence of a negatively charged PLE block enhances the biological properties of the conjugates additionally with respect to PEG20k-Nter-hGH.

2.
Mol Pharm ; 17(4): 1237-1247, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32129629

RESUMO

DNA vaccinations are promising strategies for treating diseases that require cellular immunity (i.e., cancer and protozoan infection). Here, we report on the use of a liposomal nanocarrier (lipid nanoparticles (LNPs)) composed of an SS-cleavable and pH-activated lipidlike material (ssPalm) as an in vivo DNA vaccine. After subcutaneous administration, the LNPs containing an ssPalmE, an ssPalm with vitamin E scaffolds, elicited a higher gene expression activity in comparison with the other LNPs composed of the ssPalms with different hydrophobic scaffolds. Immunization with the ssPalmE-LNPs encapsulating plasmid DNA that encodes ovalbumin (OVA, a model tumor antigen) or profilin (TgPF, a potent antigen of Toxoplasma gondii) induced substantial antitumor or antiprotozoan effects, respectively. Flow cytometry analysis of the cells that had taken up the LNPs in draining lymph nodes (dLNs) showed that the ssPalmE-LNPs were largely taken up by macrophages and a small number of dendritic cells. We found that the transient deletion of CD169+ macrophages, a subpopulation of macrophages that play a key role in cancer immunity, unexpectedly enhanced the activity of the DNA vaccine. These data suggest that the ssPalmE-LNPs are effective DNA vaccine carriers, and a strategy for avoiding their being trapped by CD169+ macrophages will be a promising approach for developing next-generation DNA vaccines.

3.
Biol Pharm Bull ; 43(1): 53-58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902932

RESUMO

The aim of the present study was to investigate the "chronotoxicity" of streptomycin (SM) in relation to its circadian periodicity. Male ICR mice were injected intraperitoneally with SM (780 mg/kg, one shot) one of six time points throughout the day. Mortality was monitored until 14 d after the injection and clearly differed depending on the timing of the injection (i.e., mice were more sensitive to injection during the dark phase). Moreover, when mice were administered with non-lethal doses of SM (550 mg/kg, every 24 h for 3 d, in the light phase or dark phase), the levels of nephrotoxicity indicators (blood urea nitrogen and renal levels of malondialdehyde and cyclooxygenase-2) were significantly increased by the injection in the dark phase, but not in the light phase. These results suggested that SM showed clear chronotoxicity. Our current data indicated that chronotoxicology may provide valuable information on the importance of injection timings for evaluations of toxicity and undesirable side effects.

4.
J Orthop Surg (Hong Kong) ; 28(1): 2309499019895636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31916479

RESUMO

PURPOSE: To compare patient subjective satisfaction between medial opening-wedge high tibial osteotomy (HTO) and total knee arthroplasty (TKA). METHODS: This study enrolled 110 knees, including comprising 49 knees in the HTO group, and 61 knees in the TKA group. We assessed the overall satisfaction using a three-point questionnaire. The satisfaction questionnaire included three questions: (1) How satisfied are you with the results of your knee surgery? (2) How satisfied are you with your most recent knee surgery for reducing your pain? and (3) How satisfied are you with your most recent knee surgery for improving your ability to perform functions? Furthermore, we assessed knee pain and function by using the Knee Society Function Score (KSS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) systems. RESULTS: Overall, 93.8% of patients from the HTO group and 95.1% from the TKA group indicated subjective satisfaction (very satisfied and satisfied) with their surgeries. For pain relief, the HTO group showed significantly better outcomes for overall satisfaction (p = 0.04 in walking on a flat surface and p = 0.02 in going upstairs or downstairs). For restored function, the HTO group scored significantly better on ascending stairs than the TKA group (p = 0.007). Functional outcomes using the KSS scoring system did not show significant differences between the two groups. The KOOS pain score was significantly higher in the TKA group (89.9 ± 6.4) than in the HTO group (80.3 ± 12.5). CONCLUSION: HTO and TKA have comparable outcomes with respect to overall patient satisfaction. LEVEL OF EVIDENCE: Level III, therapeutic case series.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31875232

RESUMO

PURPOSE: To investigate the effect of proximal tibial tubercle osteotomy (PTO) and distal tibial tubercle osteotomy (DTO) in medial opening wedge high tibial osteotomy on patellofemoral alignment, patellofemoral osteoarthritis and clinical outcomes. METHODS: PTO (n = 41) and DTO (n = 43) for the same surgical indications were included. Radiographic measurements of the Caton-Deschamps index, patellar tilt and shift, and arthroscopic cartilage evaluation at the patellofemoral joint were performed at osteotomy and plate removal. The Knee Society Score (KSS) was evaluated preoperatively and at the latest follow-up. RESULTS: The follow-up period was longer in the PTO group (33.7 months; range 23-40 years) than in the DTO group (22.2 months; range 18-29 months) (p < 0.0001), whereas the period from osteotomy to plate removal was not different between the groups. The Caton-Deschamps index of the DTO group was unchanged from 0.9 (range 0.7-1.2) to 0.9 (range 0.6-1.4), whereas that of the PTO group changed from 0.9 (0.7-1.2) to 0.7 (0.5-1.0) (p < 0.0001). There were fewer deteriorated cases of cartilage status in the trochlear groove in the DTO group (20.9%) than in the PTO group (56.1%, p < 0.05). There were more improved cases in the DTO group (23.3%) than in the PTO group (4.9%, p < 0.05). Postoperative KSS was better in the DTO group than in the PTO group (p < 0.05). CONCLUSION: DTO is associated not only with reduced deterioration but also with increased improvement of cartilage status in the trochlear groove and better KSS as compared with PTO. LEVEL OF EVIDENCE: IV.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31748918

RESUMO

PURPOSE: The purpose of this study was to evaluate the clinical outcomes and meniscus healing after arthroscopic repair of horizontal-cleavage meniscus tears, compared with vertical-longitudinal meniscus tears. METHODS: This was a retrospective review of a consecutive series of 52 meniscal repairs for horizontal-cleavage tears (n = 27) or vertical-longitudinal tears (n = 25); the groups were compared with respect to clinical symptoms and meniscal healing. Arthroscopic meniscal repair was performed using the inside-out technique with a marrow-stimulating technique. Clinical symptoms were evaluated using the Lysholm score and Knee injury and osteoarthritis outcome score (KOOS). Meniscus healing was evaluated by MRI. RESULTS: The mean follow-up periods were 35.4 ± 8.9 months in the horizontal-cleavage tear group and 39.8 ± 8.3 months in the vertical-longitudinal tear group. There were no significant differences in Lysholm score and KOOS, including each subscale, between the horizontal-cleavage tear- and vertical-longitudinal tear-groups at the final follow-up. At the final follow-up, MRI meniscus grades 0 and 1 were significantly more frequent in the vertical-longitudinal tear-group than in the horizontal-cleavage tear-group, while grade 3 was significantly more frequent in the horizontal-cleavage tear group than in the vertical-longitudinal tear group (p < 0.0001). CONCLUSIONS: Although meniscus healing of horizontal-cleavage tears may be poor, arthroscopic repair should be considered for horizontal-cleavage tears because it does provide good clinical outcomes. LEVEL OF EVIDENCE: IV.

7.
Transl Oncol ; 12(12): 1574-1582, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31671317

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high invasive and metastatic potential. We generated a spontaneous PDAC mouse model and examined the therapeutic potential of indirubin 3'-oxime (Indox) against PDAC bearing mouse in vivo. METHODS: Randomized 3-month-old LSL-KrasG12D/+;Trp53flox/+;Pdx-1-cre (KPCflox) mice were intraperitoneally injected with 40 mg/kg Indox (n = 9) or a vehicle (n = 10) twice a week. At the end point, tumor status including proliferation, direct invasion, and distant metastasis was analyzed histopathologically. The inhibitory potentials of Indox for proliferation, migration/invasion, and the phosphorylation of target molecules were determined in KPCflox-derived PDAC cells in vitro. RESULTS: Prolonged survival by Indox via intraperitoneal administration was observed in the KPCflox mice. Indox inhibited tumor proliferation accompanied with low levels of nuclear phosphorylated cyclin-dependent kinase (p-CDK) and cyclin B1 in vivo. Furthermore, Indox inhibited the migration/invasive activities of PDAC via down-regulation of matrix metalloproteinase (MMP)-9 in vitro and in vivo. Antibody array and immunoblotting analysis revealed that Indox inhibited the phosphorylation of multiple molecules, including key upstream proteins of MMP-9 in RAF/extracellular signal-regulated kinase (ERK), AKT, and stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) pathways. CONCLUSION: Indox inhibited the proliferative, invasive, and metastatic potentials of PDAC in vitro and in vivo. Therefore, Indox could a therapeutic candidate for treating spontaneously occurring PDAC via blocking the RAF/ERK, AKT and SAPK/JNK pathways.

8.
Sci Rep ; 9(1): 15692, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666582

RESUMO

Spectral vegetation index time series data, such as the normalized difference vegetation index (NDVI), from moderate resolution, polar-orbiting satellite sensors have widely been used for analysis of vegetation seasonal dynamics from regional to global scales. The utility of these datasets is often limited as frequent/persistent cloud occurrences reduce their effective temporal resolution. In this study, we evaluated improvements in capturing vegetation seasonal changes with 10-min resolution NDVI data derived from Advanced Himawari Imager (AHI), one of new-generation geostationary satellite sensors. Our analysis was focused on continuous monitoring sites, representing three major ecosystems in Central Japan, where in situ time-lapse digital images documenting sky and surface vegetation conditions were available. The very large number of observations available with AHI resulted in improved NDVI temporal signatures that were remarkably similar to those acquired with in situ spectrometers and captured seasonal changes in vegetation and snow cover conditions in finer detail with more certainty than those obtained from Visible Infrared Imaging Radiometer Suite (VIIRS), one of the latest polar-orbiting satellite sensors. With the ability to capture in situ-quality NDVI temporal signatures, AHI "hypertemporal" data have the potential to improve spring and autumn phenology characterisation as well as the classification of vegetation formations.

9.
BMC Genomics ; 20(1): 852, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727022

RESUMO

BACKGROUND: Cleft lip (CL), one of the most common congenital birth defects, shows considerable geographic and ethnic variation, with contribution of both genetic and environmental factors. Mouse genetic studies have identified several CL-associated genes. However, it remains elusive how these CL-associated genes are regulated and involved in CL. Environmental factors may regulate these genes at the post-transcriptional level through the regulation of non-coding microRNAs (miRNAs). In this study, we sought to identify miRNAs associated with CL in mice. RESULTS: Through a systematic literature review and a Mouse Genome Informatics (MGI) database search, we identified 55 genes that were associated with CL in mice. Subsequent bioinformatic analysis of these genes predicted that a total of 33 miRNAs target multiple CL-associated genes, with 20 CL-associated genes being potentially regulated by multiple miRNAs. To experimentally validate miRNA function in cell proliferation, we conducted cell proliferation/viability assays for the selected five candidate miRNAs (miR-124-3p, let-7a-5p, let-7b-5p, let-7c-5p, and let-7d-5p). Overexpression of miR-124-3p, but not of the others, inhibited cell proliferation through suppression of CL-associated genes in cultured mouse embryonic lip mesenchymal cells (MELM cells) isolated from the developing mouse lip region. By contrast, miR-124-3p knockdown had no effect on MELM cell proliferation. This miRNA-gene regulatory mechanism was mostly conserved in O9-1 cells, an established cranial neural crest cell line. Expression of miR-124-3p was low in the maxillary processes at E10.5, when lip mesenchymal cells proliferate, whereas it was greatly increased at later developmental stages, suggesting that miR-124-3p expression is suppressed during the proliferation phase in normal palate development. CONCLUSIONS: Our findings indicate that upregulated miR-124-3p inhibits cell proliferation in cultured lip cells through suppression of CL-associated genes. These results will have a significant impact, not only on our knowledge about lip morphogenesis, but also on the development of clinical approaches for the diagnosis and prevention of CL.

10.
Sci Rep ; 9(1): 14373, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591413

RESUMO

The male reproductive system is being recognized as toxic targets of nanoparticles including titanium dioxide nanoparticles (TiNP). Most of these reports are, however, obtained from the results of long-term exposure of TiNP. In this study, we diversely examined the acute effects of TiNP on the male reproductive system. Male C57BL/6J mice were administered a single intravenous injection of TiNP (10, 50 mg/kg), and were sacrificed at 1, 3, and 9 days post-injection. Testicular functions (estimated by sperm motility and sperm number) were measured via computer-assisted sperm analysis (CASA). Results indicated that sperm motility was significantly reduced from 1 day following TiNP injection (in both dose), and this reduction persisted up to 9 days post-TiNP injection (10 mg/kg injection group). Interestingly, we observed no significant decrease in sperm numbers in both the testis and the cauda epididymis in either treatment groups during the course of the experiment. Therefore, we hypothesized that TiNP may target the mature spermatozoa. In addition, sperm suspensions directly incubated with TiNP showed reduced sperm motility, [3H]-thymidine incorporation, and ATP level. Our results indicated that TiNP possesses "biphasic effects"; the obstacles to mature sperms (short term effect) in addition to the impairment in testis (long-term effect).

11.
Brief Bioinform ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589286

RESUMO

Cleft palate (CP) is the second most common congenital birth defect. The etiology of CP is complicated, with involvement of various genetic and environmental factors. To investigate the gene regulatory mechanisms, we designed a powerful regulatory analytical approach to identify the conserved regulatory networks in humans and mice, from which we identified critical microRNAs (miRNAs), target genes and regulatory motifs (miRNA-TF-gene) related to CP. Using our manually curated genes and miRNAs with evidence in CP in humans and mice, we constructed miRNA and transcription factor (TF) co-regulation networks for both humans and mice. A consensus regulatory loop (miR17/miR20a-FOXE1-PDGFRA) and eight miRNAs (miR-140, miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-451a and miR-92a) were discovered in both humans and mice. The role of miR-140, which had the strongest association with CP, was investigated in both human and mouse palate cells. The overexpression of miR-140-5p, but not miR-140-3p, significantly inhibited cell proliferation. We further examined whether miR-140 overexpression could suppress the expression of its predicted target genes (BMP2, FGF9, PAX9 and PDGFRA). Our results indicated that miR-140-5p overexpression suppressed the expression of BMP2 and FGF9 in cultured human palate cells and Fgf9 and Pdgfra in cultured mouse palate cells. In summary, our conserved miRNA-TF-gene regulatory network approach is effective in detecting consensus miRNAs, motifs, and regulatory mechanisms in human and mouse CP.

12.
Biol Pharm Bull ; 42(9): 1562-1568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474716

RESUMO

Chronopharmacology is the study of the varying responses of drugs to changes in biological timing and endogenous periodicities. The dipeptidyl peptidase-4 inhibitor sitagliptin is a globally prescribed anti-hyperglycemic drug. Although dipeptidyl peptidase-4 inhibitors are usually administered once, the specific intake time is generally not mentioned. Therefore, this study aimed at investigating the diurnal effects of sitagliptin-induced anti-hyperglycemia in high-fat diet (HFD)-induced obesity in mice. Five-week-old male C57BL/6J mice were fed normal (control) diet or HFD for 10 weeks. During the last 2 weeks, the mice were administered saline or sitagliptin (10 mg/kg, per os) in the light or dark phase, respectively. At the end of the experiment, the mice were euthanized after an 18 h fasting period, and plasma and tissue samples (liver, kidney, and epididymal white adipose tissues) were collected, or the oral glucose tolerance test was performed. Sitagliptin administration in the light phase significantly decreased plasma glucose levels, insulin levels, hepatic steatosis, and restored the glucose tolerance compared with the HFD group. In contrast, these parameters remained unchanged in the dark phase-treated mice. Our data therefore suggests that sitagliptin portrays definite chronopharmacology, which may provide valuable information on the importance of drug administration timing for maximum pharmacological effects.


Assuntos
Cronoterapia Farmacológica , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Fosfato de Sitagliptina/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Glicemia/análise , Dieta Hiperlipídica , Modelos Animais de Doenças , Glucose/metabolismo , Hiperglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/sangue , Tamanho do Órgão/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico
13.
Development ; 146(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31558435

RESUMO

It has been long appreciated that sex hormone receptors are expressed in various non-gonadal organs. However, it remains unclear how sex hormones regulate the morphogenesis of these non-gonadal organs. To address this issue, we used a male mouse model of androgen-dependent salivary gland morphogenesis. Mice with excessive cholesterol synthesis in the salivary glands exhibited defects in the maturation of granular convoluted tubules (GCTs), which is regulated through sex hormone-dependent cascades. We found that excessive cholesterol synthesis resulted in autophagy failure specifically in the duct cells of salivary glands, followed by the accumulation of NRF2, a transcription factor known as one of the specific substrates for autophagy. The accumulated NRF2 suppressed the expression of Foxa1, which forms a transcriptional complex with the androgen receptor to regulate target genes. Taken together, our results indicate that cholesterol metabolism plays a crucial role in GCT differentiation through autophagy.

14.
J Control Release ; 310: 36-46, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31386869

RESUMO

A dendritic cells (DCs)-based vaccine (DC-vaccine) system is an attractive technology for eliciting antigen-specific immune responses that can protect subjects from infectious diseases and for curing various types of cancers. For the insertion of a foreign antigen to DCs, the transfection of an antigen-coding mRNA to the cells is a promising approach. In order to introduce an antigen, a carrier for mRNA transfection is required, since the mRNA molecule per se is unstable in serum-containing medium. We previously reported on an ionizable lipid-like material with vitamin E-scaffolds (ssPalmE) as a material for a lipid nanoparticle (LNP)-based carrier for nucleic acids. In the present study, we report on the development of a lipoplex-type mRNA carrier for use as a DC-vaccine by using a combination of an ssPalmE-LNP and an α-helical cationic peptide "KALA" (ssPalmE-KALA). The transfection of mRNAs complexed with the ssPalmE-KALA achieved a significantly higher protein expression and the production of proinflammatory cytokines from murine bone marrow derived DCs (BMDCs) in comparison with a lipoplex that was prepared with an ssPalm with fatty acid-scaffolds (myristic acid; ssPalmM-KALA). A cellular uptake process and a pH-responsive membrane-destabilization activity cannot explain the preferred protein expression and immune-stimulation caused by the ssPalmE-KALA. Proteomic analyses suggest that transfection with the ssPalmM-KALA stimulates a down-regulatory pathway of translation, while the transfection with the ssPalmE-KALA does not stimulate it. In the vaccination with the BMDCs that were preliminarily transfected with an ovalbumin (OVA)-encoding mRNA elicited the induction OVA specific cytotoxic T-lymphocyte activity in vivo. In parallel, the vaccination induced significant prophylactic anti-tumor effects against a model tumor that stably expressed the OVA protein. Based on the above findings, the ssPalmE-KALA appears to be a potent ex vivo DCs-based RNA vaccine platform.

15.
Obes Res Clin Pract ; 13(5): 505-510, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31466832

RESUMO

Chronopharmacology is the study of the varying responses of drugs to changes in biological timing and endogenous periodicities. The selective sodium-glucose cotransporter 2 inhibitor, dapagliflozin, is a globally prescribed antihyperglycemic drug. Although dapagliflozin is usually administered once a day, the specific intake time is generally not mentioned. Therefore, this study aimed at investigating the diurnal effects of dapagliflozin on high-fat diet (HFD)-induced obesity in mice. Five-week-old male C57BL/6J mice were fed a normal (control) diet or HFD for 10 weeks. During the last 2 weeks, the mice were administered olive oil/ethanol emulsion or dapagliflozin (1mg/kg, p.o.) in the light or dark phase. At the end of the experiment, the mice were euthanized after an 18h fasting period, and plasma and tissue samples (epididymal white adipose tissues, liver, and kidney) were collected. Dapagliflozin administration in the light phase significantly decreased plasma glucose levels, insulin levels, adipose adipokines, and decreased the size of adipocytes, compared with the HFD group. In contrast, these parameters remained unchanged in the mice treated during the dark phase. Our data therefore suggests that dapagliflozin portrays definite chronopharmacology, which may provide valuable information on the importance of drug administration timing for maximal pharmacological effects.

16.
Biol Pharm Bull ; 42(2): 299-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713260

RESUMO

While the use of in vitro-transcribed mRNA (IVT-mRNA) in therapeutics is a rapidly expanding area, the transfection of the exogenous IVT-mRNA is accompanied by a risk of immune activation. This immunological defense mechanism suppresses cellular translation process and can reduce transfection efficiency to a considerable extent. In the present study, we investigated the in vitro effects of Integrated Stress Response Inhibitor (ISRIB), and dexamethasone, a steroidal anti-inflammatory drug, on the transfection activity of a lipid nanoparticle (LNP) that was composed of ionizable lipids and IVT-mRNA. In the case of transfection to mouse embryonic fibroblast (MEF) cells, ISRIB mainly enhanced the transfection activity at an early stage of transfection (0-6 h). In contrast, dexamethasone caused an increase in transfection activity at intermediate-late stages of transfection (4-48 h). We also investigated the in vivo effects of dexamethasone using an LNP on that the IVT-mRNA and lipid-conjugated dexamethasone (Dex-Pal) were co-loaded. The intravenous administration of the LNP successfully enhanced the protein expression in a mouse liver by up to 6.6-fold. Collectively, the co-delivery of an anti-inflammatory drug is a promising approach for enhancing transfection efficiency of IVT-mRNA.


Assuntos
Anti-Inflamatórios/farmacologia , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , RNA Mensageiro/administração & dosagem , Transfecção/métodos , Acetamidas/farmacologia , Animais , Linhagem Celular , Cicloexilaminas/farmacologia , Dexametasona/farmacologia , Fibroblastos , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química
17.
Heliyon ; 4(12): e00959, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30555953

RESUMO

An mRNA gene therapy represents a potentially promising therapeutic for curing inflammatory diseases. The transient nature of the gene expression of mRNA would be expected to be beneficial for avoiding undesired side effects. Since the mRNA is a vulnerable molecule, a development of a carrier that can deliver the mRNA to the cytoplasm has a high priority. We report herein on the development of a system for delivering mRNA to the inflammatory lesion in a dextran sulfate sodium (DSS)-induced colitis model. We modulated molecular structures of an ionizable lipid, an SS-cleavable and pH-activated lipid-like material (ssPalm). Among the fatty acids investigated, oleic acid scaffolds (ssPalmO) appeared to be more biocompatible than either myristic acid or linoleic acid scaffolds with the colitis model. The structural modification of the hydrophilic head groups from linear tertiary amines to piperazine rings (ssPalmO-Paz4-C2) resulted in a more than 10-fold higher increasing in the transgene activity in inflammatory colon. The most notable observation is that the transgene activity in the inflammatory colon is significantly higher than that in liver, the major clearance organ of lipid nanoparticles. Collectively, the ssPalmO-Paz4-C2 represents a promising material for the delivery of an mRNA to inflammatory lesions.

18.
Environ Health Prev Med ; 23(1): 49, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322375

RESUMO

BACKGROUND: The current study aimed to investigate the hepatoprotective effects of Sasa veitchii extract (SE) on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. METHODS: Male C57BL/6J mice were intraperitoneally injected with CCl4 dissolved in olive oil (1 g/kg) twice per week for 8 weeks. SE (0.1 mL) was administered orally once per day throughout the study, and body weight was measured weekly. Seventy-two hours after the final CCl4 injection, mice were euthanized and plasma samples were collected. The liver and kidneys were collected and weighed. RESULTS: CCl4 administration increased liver weight, decreased body weight, elevated plasma alanine aminotransferase, and aspartate aminotransferase and increased liver oxidative stress (malondialdehyde and glutathione). These increases were attenuated by SE treatment. Overexpression of tumor necrosis factor-α was also reversed following SE treatment. Furthermore, CCl4-induced increases in α-smooth muscle actin, a marker for hepatic fibrosis, were attenuated in mice treated with SE. Moreover, SE inhibited CCl4-induced nuclear translocation of hepatic nuclear factor kappa B (NF-κB) p65 and phosphorylation of mitogen-activated protein kinase (MAPK). CONCLUSION: These results suggested that SE prevented CCl4-induced hepatic fibrosis by inhibiting the MAPK and NF-κB signaling pathways.


Assuntos
Tetracloreto de Carbono/toxicidade , Cirrose Hepática/tratamento farmacológico , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Sasa/química , Animais , Cirrose Hepática/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
19.
Biomed Res ; 39(5): 251-260, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333432

RESUMO

The present study aimed to investigate the protective effects of kamebakaurin (KA) and 1O, 20O-diacetyl kamebakaurin (Ac2KA) on acetaminophen (APAP)-induced hepatotoxicity and compare the hepatoprotective mechanisms of the two chemicals. Seven-week-old male C57BL/6J mice were orally administered KA, Ac2KA, or an ethanol/olive oil emulsion once per day for 7-days. Twenty-four hours after the final administration, the mice were fasted and then intraperitoneally injected with 450 mg/kg APAP or saline. At 16 h after injection, the mice were euthanized and blood samples were collected for plasma analysis. Pretreatment with KA and Ac2KA significantly attenuated APAP-induced hepatic injury. The protective effect of Ac2KA was stronger than that of KA. These two chemicals attenuated oxidative stress, inflammatory cytokine production, c-jun N-terminal kinase activation, and receptor-interacting protein (RIP)-3 activation. Ac2KA also decreased APAP-induced RIP-1 activation and nuclear factor kappa B (NF-κB) p65 translocation. Moreover, Ac2KA repressed mRNA expression of Cyp1a2/2e1 in the liver. Our results showed that KA and Ac2KA exerted protective effects against APAP-induced hepatotoxicity. The responsible mechanisms may be related to the chemicals' antioxidant activity and the inhibition of c-jun N-terminal kinase activation and RIP-3 activation. The effects of Ac2KA included those of KA, as well as RIP-1 inactivation, NF-κB inhibition, and Cyp inhibition.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diterpenos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Biomarcadores , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Diterpenos/química , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Testes de Função Hepática , Masculino , Malondialdeído/metabolismo , Camundongos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismo
20.
Nanomedicine ; 14(8): 2587-2597, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30170077

RESUMO

Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE). The pDNA-encapsulating LNP (ssPalmE-LNP) induced a high interferon-ß production in Raw 264.7 cells. The subcutaneous injection of ssPalmE-LNP strongly enhanced antigen-specific cytotoxic T cell activity. The ssPalmE-LNP treatment efficiently induced antitumor effects against E.G7-OVA tumor and B16-F10 melanoma metastasis. Furthermore, when combined with an anti-programmed death 1 antibody, an extensive therapeutic antitumor effect was observed. Therefore, the ssPalmE-LNP is a promising carrier of adjuvants for cancer immunotherapy.


Assuntos
Anticorpos Monoclonais/farmacologia , DNA/química , Imunoterapia , Lipídeos/química , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Vitamina E/administração & dosagem , Adjuvantes Imunológicos , Animais , Anticorpos Monoclonais/administração & dosagem , Células Cultivadas , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/administração & dosagem , Lipossomos/química , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Vitamina E/química
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