Delivering minocycline into brain endothelial cells with liposome-based technology.
Ontology highlight
ABSTRACT:
SUBMITTER: Xing C
PROVIDER: S-EPMC3367232 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
Publications
Delivering minocycline into brain endothelial cells with liposome-based technology.
Xing Changhong C Levchenko Tatyana T Guo Shuzhen S Stins Monique M Torchilin Vladimir P VP Lo Eng H EH
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20120411 6
Minocycline has been proposed as a way to blunt neurovascular injury from matrix metalloproteinases (MMPs) during stroke. However, recent clinical trials suggest that high levels of minocycline may have deleterious side-effects. Here, we showed that very high minocycline concentrations damage endothelial cells via calpain/caspase pathways. To alleviate this potential cytotoxicity, we encapsulated minocycline in liposomes. Low concentrations of minocycline could not reduce tumor necrosis factor α ...[more]
Similar Datasets
Project description:Immune protection against infectious diseases is most effective if located at the portal of entry of the pathogen. Hence, there is an increasing demand for vaccine formulations that can induce strong protective immunity following oral, respiratory, or genital tract administration. At present, only few mucosal vaccines are found on the market, but recent technological advancements and a better understanding of the principles that govern priming of mucosal immune responses have contributed to a more optimistic view on the future of mucosal vaccines. Compared to live attenuated vaccines, subcomponent vaccines, most often protein-based, are considered safer, more stable, and less complicated to manufacture, but they require the addition of nontoxic and clinically safe adjuvants to be effective. In addition, another limiting factor is the large antigen dose that usually is required for mucosal vaccines. Therefore, the combination of mucosal adjuvants with the recent progress in nanoparticle technology provides an attractive solution to these problems. In particular, the liposome technology is ideal for combining protein antigen and adjuvant into an effective mucosal vaccine. Here, we describe and discuss recent progress in nanoparticle formulations using various types of liposomes that convey strong promise for the successful development of the next generation of mucosal vaccines.
| S-EPMC5227169 | biostudies-literature
Project description:OBJECTIVE:To provide comprehensive data to understand mechanisms of vascular endothelial cell (VEC) response to hypoxia/re-oxygenation. METHODS:Human umbilical vein endothelial cells (HUVECs) were employed to construct hypoxia/re-oxygenation-induced VEC transcriptome profiling. Cells incubated under 5% O2, 5% CO2, and 90% N2 for 3 h followed by 95% air and 5% CO2 for 1 h were used in the hypoxia/re-oxygenation group. Those incubated only under 95% air and 5% CO2 were used in the normoxia control group. RESULTS:By using a well-established microarray chip consisting of 58 339 probes, the study identified 372 differentially expressed genes. While part of the genes are known to be VEC hypoxia/re-oxygenation-related, serving as a good control, a large number of genes related to VEC hypoxia/re-oxygenation were identified for the first time. Through bioinformatic analysis of these genes, we identified that multiple pathways were involved in the reaction. Subsequently, we applied real-time polymerase chain reaction (PCR) and western blot techniques to validate the microarray data. It was found that the expression of apoptosis-related proteins, like pleckstrin homology-like domain family A member 1 (PHLDA1), was also consistently up-regulated in the hypoxia/re-oxygenation group. STRING analysis found that significantly differentially expressed genes SLC38A3, SLC5A5, Lnc-SLC36A4-1, and Lnc-PLEKHJ1-1 may have physical or/and functional protein-protein interactions with PHLDA1. CONCLUSIONS:The data from this study have built a foundation to develop many hypotheses to further explore the hypoxia/re-oxygenation mechanisms, an area with great clinical significance for multiple diseases.
| S-EPMC7183444 | biostudies-literature
Project description:Delivering nucleic acids into the endothelium has great potential in treating vascular diseases. However, endothelial cells, which line the vasculature, are considered as sensitive in nature and hard to transfect. Low transfection efficacies in endothelial cells limit their potential therapeutic applications. Towards improving the transfection efficiency, we made an effort to understand the internalization of lipoplexes into the cells, which is the first and most critical step in nucleic acid transfections. In this study, we demonstrated that the transient modulation of caveolae/lipid rafts mediated endocytosis with the cholesterol-sequestrating agents, nystatin, filipin III, and siRNA against Cav-1, which significantly increased the transfection properties of cationic lipid-(2-hydroxy-N-methyl-N,N-bis(2-tetradecanamidoethyl)ethanaminium chloride), namely, amide liposomes in combination with 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (AD Liposomes) in liver sinusoidal endothelial cells (SK-Hep1). In particular, nystatin was found to be highly effective with 2-3-fold enhanced transfection efficacy when compared with amide liposomes in combination with Cholesterol (AC), by switching lipoplex internalization predominantly through clathrin-mediated endocytosis and macropinocytosis.
| S-EPMC8346983 | biostudies-literature
Project description:BackgroundMicroparticles (MPs) are small extracellular plasma membrane particles shed by activated and apoptotic cells, which are involved in the development of atherosclerosis. Our previous study found that microRNA (miR)-19b encapsulated within endothelial MPs (EMPs) may contribute to the upregulation of circulating miR-19b in unstable angina patients. Hypoxia is involved in atherosclerosis as a critical pathological stimulus. However, it still remains unclear whether the increase of miR-19b levels in EMPs is related to hypoxia and if the effect of miR-19b - wrapped within EMPs - stimulates hypoxia on vascular endothelial cells. This study aimed to explore the changes of miR-19b in EMPs induced by hypoxia as well as their effects on endothelial cells.MethodsHuman umbilical vein endothelial cells (HUVECs) were cultured in vitro and arranged to harvest EMPs in two parts: the first part consisted of EMPcontrol and EMPhypoxia and the second part included EMPvehicle, EMPNC mimic, and EMPmiR-19b mimic. Cell migration was detected by scratch migration and transwell chamber migration. Angiogenesis was assessed by tube formation assays. Furthermore, we predicted the target gene of miR-19b by bioinformatics analysis, and luciferase assay was used to verify the targeted gene of miR-19b. Data were analyzed by one-way analysis of variance. Student's t-test was used when two groups were compared.ResultsCompared with EMPcontrol- and EMPhypoxia-inhibited migration of cells by scratch migration assay (80.77 ± 1.10 vs. 28.37 ± 1.40, P < 0. 001) and transwell chamber migration assay (83.00 ± 3.46 vs. 235.00 ± 16.52, P < 0.01), the number of tube formations was markedly reduced by 70% in the EMPhypoxia group (P < 0.001) in vitro analysis of HUVECs. Meanwhile, a strong inhibition of migration and tube formation of HUVECs in the presence of miR-19b-enriched EMPmiR-19b mimic was observed. This effect might be due to the delivery of miR-19b in EMPs. Transforming growth factor-?2 (TGF?2) was predicted to be one of the target genes of miR-19b, and we further confirmed that TGF?2 was a direct target gene of miR-19b using the luciferase assay. The expression of TGF?2 in HUVECs was inhibited by treatment with EMPhypoxia and EMPmiR-19b mimic.ConclusionsMiR-19b in EMPs induced by hypoxia could reduce endothelial cell migration and angiogenesis by downregulating TGF?2 expression, which may have inhibited the progression of atherosclerosis.
| S-EPMC6247585 | biostudies-literature
Project description:The utilization of technology has allowed for several advances in aphasia rehabilitation for individuals with acquired brain injury. Thirty-one previous studies that provide technology-based language or language and cognitive rehabilitation are examined in terms of the domains addressed, the types of treatments that were provided, details about the methods and the results, including which types of outcomes are reported. From this, we address questions about how different aspects of the delivery of treatment can influence rehabilitation outcomes, such as whether the treatment was standardized or tailored, whether the participants were prescribed homework or not, and whether intensity was varied. Results differed by these aspects of treatment delivery but ultimately the studies demonstrated consistent improvement on various outcome measures. With these aspects of technology-based treatment in mind, the ultimate goal of personalized rehabilitation is discussed.
| S-EPMC5532441 | biostudies-other
Project description:INTRODUCTION:The educational technology of massive open online courses (MOOCs) has been successfully applied in a wide variety of disciplines and are an intense focus of educational research at this time. Educators are now looking to MOOC technology as a means to improve professional medical education, but very little is known about how medical MOOCs compare with traditional content delivery. METHODS:A retrospective analysis of the course evaluations for the Medicine as a Business elective by fourth-year medical students at Southern Illinois University School of Medicine (SIU-SOM) for the 2012-2015 academic years was conducted. This course was delivered by small group flipped classroom discussions for 2012-2014 and delivered via MOOC technology in 2015. Learner ratings were compared between the two course delivery methods using routinely collected course evaluations. RESULTS:Course enrollment has ranged from 6-19 students per year in the 2012-2015 academic years. Student evaluations of the course are favorable in the areas of effective teaching, accurate course objectives, meeting personal learning objectives, recommending the course to other students, and overall when rated on a 5-point Likert scale. The majority of all student ratings (76-95%) of this elective course are for the highest possible choice (Strongly agree or Excellent) for any criteria, regardless if the course was delivered via a traditional or MOOC format. Statistical analysis of these ratings suggests that the Effective Teacher and Overall Evaluations did not statistically differ between the two delivery formats. DISCUSSION:Student ratings of this elective course were highly similar when delivered in a flipped classroom format or by using MOOC technology. The primary advantage of this new course format is flexibility of time and place for learners, allowing them to complete the course objectives when convenient for them. The course evaluations suggest this is a change that is acceptable to the target audience. CONCLUSIONS:This study suggests that learner evaluations of a fourth-year medical school elective course do not significantly differ when delivered by flipped classroom group discussions or via MOOC technology in a very small single center observational study. Further investigation is required to determine if this delivery method is an acceptable and effective means of teaching in the medical school environment.
| S-EPMC4991885 | biostudies-literature
Project description:Lipid nanoparticles have transformed the drug delivery field enhancing the therapeutic drug performance of small molecules and biologics with several approved drug products. However, in industry, these more complex drug delivery systems such as liposomes require more material and time to develop. Here, we report a liposome and lipodisk decision tree with model compounds of diverse physicochemical properties to understand how to resourcefully optimize encapsulation efficiency (EE) for these lipid-based drug delivery systems. We have identified trends with physicochemical properties such as Log P, where higher Log P compounds such as curcumin were able to efficiently load into the lipid bilayer resulting in high EE with altering the drug/lipid (D/L) ratio. Moderate Log P compounds such as cyclosporine A and dexamethasone had significantly higher encapsulation in lipodisks, which contain higher amounts of PEG lipid compared to liposomes. The EE of negative Log P compounds, like acyclovir, remained low regardless of altering the D/L ratio and PEG concentrations. In this study, microfluidic techniques were employed to fabricate liposomes and lipodisks formulations allowing for a reproducible strategy for formulation development. Both liposome and lipodisk of curcumin demonstrated enhanced in vivo performance compared with a conventional formulation in the rat pharmacokinetic study. This combination of approaches with multiple model compounds and lipid-based drug delivery systems provides a systematic guidance to effective strategies to generate higher EE with minimal drug waste and expedite the process for preclinical development when applied to industry compounds.
| S-EPMC8516330 | biostudies-literature
Project description:Minocycline-based combination therapy has been suggested to be a possible choice for the treatment of infections caused by minocycline-susceptible Acinetobacter baumannii, but its use for the treatment of infections caused by minocycline-resistant A. baumannii is not well established. In this study, we compared the efficacy of minocycline-based combination therapy (with colistin, cefoperazone-sulbactam, or meropenem) to that of colistin in combination with meropenem for the treatment of minocycline-resistant A. baumannii infection. From 2006 to 2010, 191 (17.6%) of 1,083 A. baumannii complex isolates not susceptible to minocycline from the Taiwan Surveillance of Antimicrobial Resistance program were collected. Four representative A. baumannii isolates resistant to minocycline, amikacin, ampicillin-sulbactam, ceftazidime, ciprofloxacin, cefepime, gentamicin, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam were selected on the basis of the diversity of their pulsotypes, collection years, health care setting origins, and geographic areas of origination. All four isolates had tetB and overexpressed adeABC, as revealed by quantitative reverse transcription-PCR. Among all minocycline-based regimens, only the combination with colistin produced a fractional inhibitory concentration index comparable to that achieved with meropenem combined with colistin. Minocycline (4 or 16 ?g/ml) in combination with colistin (0.5 ?g/ml) also synergistically killed minocycline-resistant isolates in time-kill studies. Minocycline (50 mg/kg of body weight) in combination with colistin (10 mg/kg) significantly improved the survival of mice and reduced the number of bacteria present in the lungs of mice compared to the results of monotherapy. However, minocycline (16 ?g/ml)-based therapy was not effective at reducing biofilm-associated bacteria at 24 or 48 h when its effectiveness was compared to that of colistin (0.5 ?g/ml) and meropenem (8 ?g/ml). The clinical use of minocycline in combination with colistin for the treatment of minocycline-resistant A. baumannii may warrant further investigation.
| S-EPMC4914616 | biostudies-literature
Project description:Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-?, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-?1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, ?1-integrin, calponin and ?-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-? signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-?-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-?-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.
| S-EPMC4350839 | biostudies-literature