A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting

Lin Zhang1*, Weiwei Zhu2*, Chunfen Yang1, Hongxia Guo1, Aihua Yu1, Jianbo Ji3, Yan Gao1, Min Sun1, Guangxi Zhai11Department of Pharmaceutical Engineering, College of Pharmacy, Shandong University, Jinan; 2Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai; 3Department of Pharmacology, College of Pharmacy, Shandong University, Jinan, China*These authors contributed equally to the workBackground: The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells.Methods: Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research.Results: The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor® EL, 32.5% Transcutol® HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells.Conclusion: FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.Keywords: curcumin, SMEDDS, folate receptor, colon targetin

Stress sensitivity evaluation of ultra-low permeability sandstone reservoir and its influence on oilfield development

Luohe ultra-low permeability sandstone reservoir is a hot block in Yanchang oilfield, which is a potential point for increasing production and reservoir. In view of the current situation that there is no unified stress sensitivity evaluation standard for ultra-low permeability sandstone in the study area, taking the ultra-low permeability sandstone in Luohe district as the research object, the stress sensitivity evaluation of ultra-low permeability sandstone is carried out by using experimental analysis as the main means. The results show that it is more accurate to evaluate porosity by using pore stress sensitivity coefficient instead of pore compressibility coefficient. With the increase of net overburden pressure, the porosity stress sensitivity decreases gradually; the permeability stress sensitivity is evaluated by variable confining pressure. With the increase of confining pressure, the permeability damage decreases. With the decrease of confining pressure, the permeability damage increases, but it can not recover to the original value, so the permeability damage is irreversible; in the low bottom hole pressure stage, stress sensitivity has a greater impact on oil well productivity, while in the high bottom hole pressure stage, stress sensitivity has a smaller impact on oil well productivity; advanced water injection can reduce the adverse effect of stress sensitivity on the development of ultra-low permeability sandstone and maximize the economic benefits. The research results clarify the method of stress sensitivity evaluation, and provide guidance for efficient water injection in the next step

Application of a new multi-element integrated teaching mode based on bite-sized teaching, flipped classroom, and MOOC in clinical teaching of obstetrics and gynaecology

Abstract Context Effective clinical medical student education includes attention to teaching approaches. This study assessed the impact of a new multi-element teaching mode that utilizes Bite-Sized Teaching, flipped classroom, and MOOC on learner perception in an Obstetrics and gynaecology clerkship. Methods A Two-stage crossover design study was conducted of a multi-element teaching mode compared to traditional teaching mode in an academic year. Participants included Ninety-six medical students practicing obstetrics and gynecology in our hospital, randomly divided into two groups respectively underwent multi-element teaching mode and traditional teaching mode. After each semester, a final test (including theoretical and clinical practical test) was conducted.When an academic year was completed, post intervention survey assessed learner perceptions of the intervention. Result In order to comprehensively test students’ performance after study, we take theoretical and practical examinations. The theoretical examination mainly tests students’ grasp of basic knowledge points, while the practical examination focuses on the examination of students’ diagnosis and treatment of diseases. There were statistically significant differences both in the theoretical and clinical practical scores between the new multi-element integrated teaching mode and the traditional teaching mode, specifically as follows: In the end of first semester, the theoretical scores of the two groups were respective 43.75 ± 3.42 vs. 42.07 ± 2.90, and clinic practical test scores were respective 44.93 ± 2.42 vs. 43.37 ± 2.52; In the end of second semester, the theoretical scores of the two groups were respective 44.30 ± 2.69 vs. 42.25 ± 3.39, and clinic practical test scores were respective 43.79 ± 2.25 vs. 41.93 ± 2.80.(p < 0.05). The results of questionnaires demonstrated that 80.21% of the students showed preference for the new multi-element integrated teaching mode comparing to traditional teaching methods. Conclusion The new multi-element integrated teaching mode is well accepted by the students and can improve the students’ mastery of knowledge, and can improve the students’ clinical comprehensive ability. The new multi-element integrated teaching mode is shown more preference than traditional teaching mode in the teaching of Obstetrics and Gynaecology. Further long term study is needed carried out to consolidate our conclusion. The new multi-element integrated teaching mode may have positive effects on clinical teaching of Obstetrics and Gynaecology

Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS

Poly(lactide-<i>co</i>-glycolide)/Fibrin Gel Construct as a 3D Model to Evaluate Gene Therapy of Cartilage in Vivo

Combination of gene therapy with tissue engineering can enhance the interplay between cells and matrix, leading to better restoration and regeneration of tissues and organs in vivo. In this study the PLGA/fibrin gel hybrids were employed to load lipofectamine/pDNA-TGF-β1 complexes and mesenchymal stem cells (MSCs) (experimental group), acting as a cartilage-mimetic tissue platform. The gene complexes distributed more evenly in the hybrid scaffolds, whereas they adhered onto the pore walls of the PLGA sponges. The filled fibrin gel rendered gene release in a slower manner, too. Moreover, the fibrin gel entrapped MSCs and contributed to a higher cell loading density in the hybrid constructs. In vivo assay showed that in the defects implanted with the experimental constructs both gene and protein expression levels of TGF-β1 were significantly higher than those of the fibrin-free group at weeks 1, 3, and 6 after surgery. The full articular cartilage defects repaired by the experimental group for 12 w were resurfaced by neo-tissues with a similar thickness, cell arrangement, and color to the normal neighboring cartilage and abundant glycosaminoglycans

Impact of Yangtze River Water Transfer on the Water Quality of the Lixia River Watershed, China

<div><p>To improve water quality and reduce the negative impacts of sudden inputs of water pollution in the Lixia River watershed, China, a series of experimental water transfers from the Yangtze River to the Lixia River were conducted from 2 December 2006 to 7 January 2007. Water samples were collected every six days at 55 monitoring sites during this period. Eight water parameters (water temperature, pH, dissolved oxygen (DO), chemical oxygen demand (COD), potassium permanganate index (COD_Mn), ammonia nitrogen (NH₄⁺-N), electrical conductivity (EC), and water transparency (WT)) were analyzed to determine changes in nutrient concentrations during water transfers. The comprehensive pollution index (Pi) and single-factor (Si) evaluation methods were applied to evaluate spatio-temporal patterns of water quality during water transfers. Water quality parameters displayed different spatial and temporal distribution patterns within the watershed. Water quality was improved significantly by the water transfers, especially for sites closer to water intake points. The degree of improvement is positively related to rates of transfer inflow and drainage outflow. The effects differed for different water quality parameters at each site and at different water transfer times. There were notable decreases in NH₄⁺-N, DO, COD, and COD_Mn across the entire watershed. However, positive effects on EC and pH were not observed. It is concluded that freshwater transfers from the Yangtze River can be used as an emergency measure to flush pollutants from the Lixia River watershed. Improved understanding of the effects of water transfers on water quality can help the development and implementation of effective strategies to improve water quality within this watershed.</p></div

Water quality parameters and their associated abbreviations, units, regulatory standards, and analytical methods.

<p>Water quality parameters and their associated abbreviations, units, regulatory standards, and analytical methods.</p