Application of deferoxamine in bone tissue regeneration / 中国组织工程研究

BACKGROUND:Aside from iron chelating,deferoxamine is also considered as an effective hypoxia mimetic agent and hypoxia inducible factor-1α stabilizer.Deferoxamine has played a favorable effect on bone regeneration in both basic and clinical research recently.Deferoxamine solutions or deferoxamine loaded bio-scaffolds have been locally applied in bone tissue engineering,and their promotion of bone repair involves various functional properties and molecular mechanisms which have not been entirely clarified.Moreover,their advances in research of bone regeneration lack comprehensive summary as well. OBJECTIVE:To review the functional properties,relative merits and advances in basic research and clinical practice of deferoxamine applied in bone regeneration,attempting to provide references and strategies for further studies. METHODS:Relevant articles were searched with the key words of"deferoxamine OR desferrioxamine OR desferal OR DFO,""bone tissue engineering OR bone regeneration OR bone remodeling OR bone repair OR bone healing OR osteogenesis,""angiogenesis OR vascularized bone regeneration OR angiogenic-osteogenic coupling"in English and Chinese by using PubMed,WanFang and CNKI databases.Eventually,88 articles were selected for review. RESULTS AND CONCLUSION:Deferoxamine can recruit stem cells and regulate their function,activate relevant signaling pathways to advance hypoxia adaptation of the cells,exert anti-inflammatory and antioxidant properties to improve local inflammatory environment,and promote bone regeneration by coupling osteogenesis and angiogenesis as well as inhibiting bone resorption.Compared with growth factors or peptides loaded in conventional bone tissue engineering,deferoxamine has its unique advantages as a small molecule drug,while it also has toxic reactions and application limitations.Therefore,it is necessary to optimize its loading form and dosagey.The unique angiogenic-osteogenic coupling ability of deferoxamine can be used in different types of bone injuries including fractures,osteonecrosis,distraction osteogenesis,bone grafting,oral related osteogenesis,and bone defects.Due to the enhancement of angiogenesis,this ability enables deferoxamine to better adapt and solve the difficulties in bone repair caused by the complex and variable clinical situations and individual differences.However,it is also necessary to compare and optimize the application methods and safe dosage of deferoxamine to expand its application scope and enhance its clinical value.

Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

Insulino Mimetic Selenium in Type II Diabetes: Correlation with Blood Glucose

Background: Selenium has been reported to be insulinomimetic and to reduce blood glucose level in type 2 diabetes.Material & Methods:This study describes an inverse correlation of serum selenium with blood glucose level. This is a case control study conducted among 30 low BMI and 70 normal BMI diabetes and 50 low BMI non-diabetic controls. Serum selenium concentration was determined by atomic absorption graphite spectrophotometry.Results:Serum selenium concentration was estimated to be 44�礸/L, 48�礸/L and 59�礸/L respectively in low BMI (<18.5) and normal BMI (18.5-24.9) diabetics and low BMI non-diabetics controls. A trend of inverse correlation was found between serum selenium and blood glucose levels. Serum selenium level at > 40 (41-60) 礸/L was found to be inversely correlated (p<0.05) with blood glucose level.Conclusions:Lower serum selenium was observed in the diabetic patients and it was inversely correlated with blood glucose level

Anti-inflammatory mechanism of annexin A1 mimetic peptide Ac2-26 on lung injury induced by cardiopulmonary bypass in rats / 中华胸心血管外科杂志

Objective:To observe the effect of annexin A1 peptidomimetic Ac2-26 on lung injury in rats with cardiopulmonary bypass, and analysis its anti-inflammatory mechanism.Methods:Eighteen male SD rats were divided into 3 groups(n=6) according to the random number table: sham operation group(S group), ischemia reperfusion group(IR group), Ac2-26 group(A group). The sham operation group received femoral arteriovenous puncture and catheterization, only the left lung was opened and the cardiopulmonary bypass tube was not connected. The other two groups were established with cardiopulmonary bypass left lung ischemia-reperfusion injury model. The IR group was given the same volume 10 minutes before cardiopulmonary bypass with the normal saline solution. Group A was injected with Ac2-26(1 mg/kg) through the tail vein 10 minutes before cardiopulmonary bypass. The arterial blood of the three groups of rats was taken for blood gas analysis before CPB(T1), immediately after opening the left lung hilum(T2), and at the end of the experiment(T3) to calculate OI and RI. At T1 and T3, the femoral vein blood was taken to measure the number of PMN. At T3, pulmonary artery blood was taken to measure the number of PMN and VCAM-1 content, left lung tissue was taken to measure NE and MPO content by ELISA, lung tissue neutrophil apoptosis was measured by Tunel method, and lung tissue ICAM-1 and AnxA1 protein expression was measured by Western-Blot.Results:At T3, compared with group S, the number of PMN in peripheral blood and pulmonary artery blood and the content of pulmonary artery VCAM-1 in IR group were significantly higher, the content of MPO and NE in lung tissue increased, the lung tissue pathological damage score increased, OI decreased and RI increased, all P<0.05. Compared with IR group, the lung tissue pathological damage score of rats in group A was significantly reduced, the number of PMN in peripheral blood and pulmonary artery blood and the content of VCAM-1 in pulmonary artery blood were significantly reduced, the expression of AnxA1 and ICAM-1 in the lung tissue of rats decreased; the content of MPO and NE in lung tissue decreased, and the apoptosis rate of PMN increased, all P<0.05. Conclusion:Ac2-26 annexin A1 peptidomimetics can inhibit the aggregation of neutrophils in the lung, weaken the adhesion of neutrophils to the pulmonary vascular endothelium, promote the apoptosis of neutrophils in the lungs, and reduce the content of NE and MPO. It has a protective effect on lung injury after cardiopulmonary bypass in rats.

Study on the inhibition and remineralization of enamel demineralization by polydopamine in vitro / 口腔疾病防治

Objective@#To investigate the inhibitory effect of polydopamine (PDA) on enamel demineralization in isolated teeth and the induction of hydroxyapatite (HA) production on the surface of demineralized enamel to provide a novel protocol for the prevention and treatment of enamel demineralization. @*Methods@#Twenty isolated bovine teeth were cut into 20 enamel slices and randomly divided into an experimental group and a control group, with 10 slices in each group. The enamel slices in the experimental group were immersed in 2 mg/mL freshly prepared dopamine solution and incubated for 24 hours at room temperature in the dark to prepare the PDA coating, while the control group was left untreated. Then, the isolated bovine teeth, with and without PDA coating, were immersed in artificial demineralization solution at 37 °C for 3 days, followed by 7 days in simulated body fluid (SBF), and the immersion solution was changed daily. The surface morphology of enamel was observed by scanning electron microscopy (SEM), the calcium/phosphorus ratio of the enamel surface was analyzed by energy dispersive spectroscopy (EDS), and the characteristic functional groups in enamel deposits were analyzed by Fourier transform infrared spectroscopy (FTIR).@* Results@#Compared with the control group, the number of demineralized pores produced after 3 d of enamel demineralization with polydopamine coating was less, and the diameter was smaller. EDS elemental analysis showed that the Ca/P ratio after enamel demineralization was 2.37 in the experimental group, which was smaller than the 2.53 ratio in the control group. In the remineralization experiment, after 7 days of remineralization of PDA coated enamel in the experimental group, lamellar grains were produced on the enamel surface, and the growth showed obvious directionality, growth regularity and uniform arrangement. In the control group, the surface of enamel was flocculent mineral deposit, and the crystallinity was poor. The FTIR results proved that the enamel surface deposit of PDA-coated enamel was HA after 7 d of remineralization. @*Conclusion @#PDA can affect the nucleation process of HA and promote the production of HA on the surface of demineralized enamel.

Application status of hypoxia mimetic agents in bone tissue engineering / 中国修复重建外科杂志

Objective: To summarize the application status of hypoxia mimetic agents in bone tissue engineering. Methods: The related literature about the hypoxia mimetic agents in bone tissue engineering was reviewed and analyzed. And the application status and progress of hypoxia mimetic agents in bone tissue engineering were retrospectively analyzed. Results: Hypoxia mimetic agents have the same effect as hypoxia in up-regulating the level of hypoxia inducible factor 1α (HIF-1α). The combination of hypoxia mimetic agents and scaffolds can up-regulate the level of HIF-1α in bone tissue engineering, thus promoting early vascularization and bone regeneration of the bone defect area, which provides a new idea for using bone tissue engineering to repair bone defect. At present, the commonly used hypoxia mimetic agents include iron chelating agents, oxoglutarate competitive analogues, proline hydroxylase inhibitors, etc. Conclusion: Hypoxia mimetic agents have a wide application prospect in bone tissue engineering, but they have been used in bone tissue engineering for a short time, more attention should be paid to their possible side effects. In the future research, the hypoxia mimetic agents should be developed in the direction of higher targeting specificity and safety, and the exact mechanism of hypoxia mimetic agents in promoting bone regeneration should be further explored.

Design and in vitro evaluation of delivery systems for co-delivery of siRNA and proteins by mimetic exosomes / 药学学报

To prepare the mimetic exosomes and co-delivery proteins and nucleic acids, and achieve efficient and safe co-delivery of multi-component drugs, an optimized formulation was designed by modifying a polylactic acid-glycolic acid copolymer (PLGA) matrix with a cationic lipid excipient dioleyl trimethylammonium propane (DOTAP), and a PLGA/DOTAP nanoparticles packaged protein and nucleic acid was prepared by double emulsion method, and the outermost membrane structure prepared by reverse phase evaporation method and consists of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol and membrane proteins. The structure of the mimetic exosomes is formed by ultrasonic dispersion and extrusion, and analyzed its characteristics and nature of the transfer effect. The size of mimetic exosomes was about 156.13 nm, with negative charge (-18.23 ± 0.57 mV), and it could efficiently co-transfer protein and siRNA, and siRNA could effectively inhibit the expression of target gene Trim28. The mimetic exosomes simulate the structure of exosomes and achieve safe and efficient co-delivery of multi-component drugs.

Experimental study on the effect of desferrioxamine on targeted homing and angiogenesis of bone marrow mesenchymal stem cells / 中国修复重建外科杂志

Objective: To investigate whether desferrioxamine (DFO) can enhance the homing of bone marrow mesenchymal stem cells (BMSCs) and improve neovascularization in random flaps of rats. Methods: BMSCs and fibroblasts (FB) of luciferase transgenic Lewis rats were isolated and cultured. Forty 4-week-old Lewis male rats were used to form a 10 cm×3 cm rectangular flap on their back. The experimental animals were randomly divided into 4 groups with 10 rats in each group: in group A, 200 μL PBS were injected through retrobulbar venous plexus; in group B, 200 μL FB with a concentration of 1×10 6 cells/mL were injected; in group C, 200 μL BMSCs with a concentration of 1×10 6 cells/mL were injected; in group D, cells transplantation was the same as that in group C, after cells transplantation, DFO [100 mg/(kg·d)] were injected intraperitoneally for 7 days. On the 7th day after operation, the survival rate of flaps in each group was observed and calculated; the blood perfusion was observed by laser speckle imaging. Bioluminescence imaging was used to detect the distribution of transplanted cells in rats at 30 minutes and 1, 4, 7, and 14 days after operation. Immunofluorescence staining was performed at 7 days after operation to observe CD31 staining and count capillary density under 200-fold visual field and to detect the expressions of stromal cell derived factor 1 (SDF-1), epidermal growth factor (EGF), fibroblast growth factor (FGF), and Ki67. Transplanted BMSCs were labeled with luciferase antibody and observed by immunofluorescence staining whether they participated in the repair of injured tissues. Results: The necrosis boundary of ischemic flaps in each group was clear at 7 days after operation. The survival rate of flaps in groups C and D was significantly higher than that in groups A and B, and in group D than in group C ( P<0.05). Laser speckle imaging showed that the blood perfusion units of flaps in groups C and D was significantly higher than that in groups A and B, and in group D than in group C ( P<0.05). Bioluminescence imaging showed that BMSCs gradually migrated to the ischemia and hypoxia area and eventually distributed to the ischemic tissues. The photon signal of group D was significantly stronger than that of other groups at 14 days after operation ( P<0.05). CD31 immunofluorescence staining showed that capillary density in groups C and D was significantly higher than that in groups A and B, and in group D than in group C ( P<0.05). The expressions of SDF-1, EGF, FGF, and Ki67 in groups C and D were significantly stronger than those in groups A and B, and in group D than in group C. Luciferase-labeled BMSCs were expressed in the elastic layer of arteries, capillaries, and hair follicles at 7 days after transplantation. Conclusion: DFO can enhance the migration and homing of BMSCs to the hypoxic area of random flap, accelerate the differentiation of BMSCs in ischemic tissue, and improve the neovascularization of ischemic tissue.

The hermeneutical dimension of the bioethical enterprise: notes on the dialogical/narrative foundations of bioethics / La dimensión hermenéutica de la empresa bioética: notas sobre el fundamento dialógico/narrativo de la bioética / A dimensão hermenêutica da empresa bioética: notas sobre a narrativa dialógica dos fundamentos da bioética

Resumen: Based on the challenges posed by the scientific activity of the author, related to the integration and harmonization of heterogeneous discourses, a hermeneutic framework for bioethics is stressed. It is mainly concerned with elucidating intentions, hidden meanings, and motivations of texts and behaviors that can be converted into texts. Equating the mimetic circle of Paul Ricoeur with the hermeneutical circle is advocated as a practical application. The importance of the hermeneutic approach suggests that it can also be applied to written productions in bioethics, since the history of this intellectual endeavor can be reformulated considering a reinterpretation of its record.

Abstract: Basándose en los desafíos de su propia trayectoria científica, relacionados con la integración y la armonización de discursos heterogéneos, se destaca el marco de referencia hermenéutico para la bioética. Se relaciona con dilucidar intenciones, significados ocultos y motivaciones de textos y conductas que pueden ser convertidas a textos. Equiparar el círculo mimético de Paul Ricoeur con el círculo hermenéutico se propone como una aplicación práctica. La importancia de la aproximación hermenéutica sugiere que también puede aplicarse a las producciones escritas de la bioética, ya que la historia de esta disciplina puede reformularse considerando una reinterpretación de su registro.

Resumo: Baseado nos desafios decorrentes da atividade científica do autor, relacionados à integração e harmonização dos discursos heterogêneos, quadro hermenêutico para a Bioética é traçado. E sua preocupação central está em elucidar intenções, significados ocultos, motivações dos textos e comportamentos que podem ser convertidos em textos. Igualar o círculo mimético de Paul Ricoeur com o círculo hermenêutico é defendida como uma aplicação prática. A importância da abordagem hermenêutica sugere que pode também ser aplicada às produções escritas em Bioética, desde que a história deste empreendimento intelectual pode ser reformulada considerando uma reinterpretação de seu registro.

Determination of Glucose Based on Carbon Quantum Dots as Peroxidase Mimetic Enzyme / 分析化学

Water soluble carbon quantum dots ( CQDs) were prepared by using soot as carbon source. The obtained CQDs showed an excellent intrinsic peroxidase-like activity, which could catalyze the oxidization of 3,3′,5,5′-tetramethylbenzidine (TMB) by H2O2and thus resulted in color change. Glucose could react with dissolved oxygen to produce H2O2in the presence of glucose oxidase ( GOx) . A colorimetric method using CQDs as peroxidase mimetic enzyme was developed for glucose determination. When TMB was acted as a substrate, the effect of a series of conditions, such as temperature and pH on the catalytic activity of the obtained CQDs, was systematically studied. Under optimal conditions, e. g. pH 3. 5 and temperature 35℃, 0. 5 mmol/L TMB and 1 μg/mL CQDs, the absorbance at 652 nm showed linear response with glucose concentrations ranging from 0. 025 mmol/L to 0. 40 mmol/L, with detection limit of 5. 10 μmol/L (3σ/k). The proposed method exhibited excellent selectivity and the common substances did not interfere with detection of glucose. This method was successfully applied to detect glucose in real samples with recoveries of 95. 0%-105. 1% .

A Sporadic Case of Epstein Syndrome: A Rare Cause of Refractory Thrombocytopenia / 대한내과학회지

A 37-year-old female presented to our hospital with a history of bleeding episodes (excessive bleeding after tooth extraction, gum bleeding, easy bruising, and excessive menstruation) and severe thrombocytopenia (2,000/µL). She had no family history of bleeding tendency or thrombocytopenia. No peripheral lymphadenopathy or splenomegaly was noted. The patient's white blood cell count was normal; hemoglobin was 9.7 g/dL. A peripheral blood smear showed markedly decreased platelets, with occasional giant or large platelets. Bone marrow examination found increased megakaryocytes. The patient also complained of hearing difficulty; a hearing test indicated sensory-neural hearing impairment. Her thrombocytopenia was refractory to treatment with glucocorticosteroids, intravenous gamma-globulin, and danazol. In the 13 years following her initial presentation, the patient required anti-hypertensive treatment, a hearing-aid for progressive hearing loss, and started maintenance kidney dialysis. Her clinical history of refractory thrombocytopenia, progressive hearing impairment, and renal failure suggested myosin heavy chain 9 gene-related congenital syndrome (Epstein syndrome), which was confirmed by the presence of a heterozygous deletion mutation, c.221_223del, (p.Lys74del) in peripheral leukocyte deoxyribonucleic acid.

Development of a novel stability indicating RP-HPLC method for quantification of Connexin43 mimetic peptide and determination of its degradation kinetics in biological fluids / 药物分析学报

Connexin43 mimetic peptide (Cx43MP) has been intensively investigated for its therapeutic effect in the management of inflammatory eye conditions, spinal cord injury, wound healing and ischemia-induced brain damage. Here, we report on a validated stability–indicating reversed-phase high performance liquid chromatography(RP-HPLC)method for the quantification of Cx43MP under stress conditions.These included exposure to acid/base, light, oxidation and high temperature. In addition, the degradation kinetics of the peptide were evaluated in bovine vitreous and drug-free human plasma at 37 ℃. Detection of Cx43MP was carried out at 214 nm with a retention time of 7.5 min. The method showed excellent linearity over the concentration range of 0.9–250μg/mL(R2≥0.998),and the limits of detection(LOD)and quantification(LOQ) were found to be 0.90 and 2.98 μg/mL, respectively. The accuracy of the method determined by the mean percentage recovery at 7.8, 62.5 and 250μg/mL was 96.79%, 98.25% and 99.06% with a RSD of<2.2%. Accelerated stability studies revealed that Cx43MP was more sensitive to basic conditions and completely degraded within 24 h at 37 ℃(0% recovery)and within 12 h at 80 ℃(0.34% recovery).Cx43MP was found to be more stable in bovine vitreous(t1/2slow=171.8 min)compared to human plasma(t1/2slow=39.3 min)at 37 ℃ according to the two phase degradation kinetic model. These findings are important for further pre-clinical development of Cx43MP.

Advances of synthetic lipoproteins as drug nanovectors / 中国药科大学学报

@#Synthetic lipoproteins are efficient nanovectors for targeting delivery of biological drugs, chemical drugs and imaging contrast agents and so on. They have ultra-small particle size, excellent biocompatibility, favorable circulation half-life and specific lipoprotein-receptors-binding capacity of lipoprotein receptors. Compared with traditional natural lipoproteins, synthetic lipoproteins possess both native biochemical properties and functions, and superior drug delivery potentials. This paper introduces the development of lipoproteins as drug nanovectors and reviews preparation methods of synthetic lipoproteins, in vitro and in vivo applications and the approaches employed to expand the limited applications of lipoproteins as drug nanovectors. Further development of synthetic lipoproteins is also proposed.

Effects of Nimodipine on Peripheral Facial Paralysis and Hearing in Mimetic Convulsion Patients after Mi-crovascular Decompression / 中国药房

OBJECTIVE:To observe the effects of nimodipine on peripheral facial paralysis and hearing in mimetic convulsion patients after microvascular decompression. METHODS:162 mimetic convulsion patients underwent microvascular decompression were enrolled in this study,and then randomly divided into control group and observation group,81 cases in each group. Control group was given routine microvascular decompression,and observation group was additionally given intravenous pump of Nimodip-ine injection 40 mg,qd,2 mg/h for consecutive 3 days after operation,and then given Nimodipine tablet 40 mg,qd,for 10 days. The incidence of peripheral facial paralysis and hearing disorder,onset time,duration time and severity of facial paralysis were ob-served in 2 groups. RESULTS:The incidence of peripheral facial paralysis and hearing disorder were 8.6% and 6.2% in observa-tion group,which were significantly lower than 14.8%and 11.1%of control group,with statistical significance(P<0.05). The on-set and duration time of peripheral facial paralysis was(15.32±3.15)d and(36.52±5.84)d in observation group,which were sig-nificantly later and lower than(12.21±2.16)d and(44.73±6.57)d of control group,with statistical significance(P<0.05). Ac-cording to House-Brackman classification method,the incidence of Ⅲ、Ⅳ facial paralysis was lower in control group than that in observation group,with statistical significance (P<0.05). CONCLUSIONS:Nimodipine can significantly decrease the incidence of peripheral facial paralysis and hearing disorder in mimetic convulsion patients after microvascular decompression,and contrib-utes to the recovery of injured nerve function.

Collagen mimetic peptide-PEG hybrid hydrogel for 3D culture of rabbit bone marrow mesenchymal stem cells / 国际生物医学工程杂志

Objective To construct a extracellular matrix-like collagen mimetic peptide-PEG hybrid hydrogel and to study the usage of this hydrogel in 3D culture of rabbit bone marrow mesenchymal stem cells (rBMSCs).Methods The hybrid hydrogel was synthesised by conjugating the cysteine at the end of the collagen mimetic peptide with the maleimine-modified multi-arm PEG.The circular dichroism spectra were used to characterize the triple helix structure and thermal stability of the collagen mimetic peptides.The rheology test and scanning electron microscopy were used to study the gelation process,mechanical strength and internal structure of the hydrogel.The rBMSCs were embedded in the hybrid hydrogel for 3D culture.The cell compatibility of the hydrogel and its effect on differentiation of the cells was studied.Results Collagen mimetic peptides could promote spontaneous formation of triple helix structure in the natural collagen,and the thermal transition temperature was 49.4 ℃.The formation process of the collagen mimetic peptides-PEG hybrid hydrogel was rapid,in which the porous network-like fibrous structure was formed.After the encapsulation of rBMSCs within the hydrogel for 24 h,most of the cells remained viable.Gene expression analysis showed that the hybrid hydrogel could affect the differentiation of rBMSCs.Conclusions The collagen mimetic peptide-PEG hybrid hydrogel possesses the characteristics of mild preparation condition,good mechanical strength and good cell compatibility,and is favorable to chondrocyte differentiation of rBMSCs.

Research progress in erythropoietin mimetic peptides / 天津医药

Erythropoietin (EPO) is an active glycoprotein synthesized by kidney. The physiological function of regulat?ing the synthesis of erythrocytes by EPO makes it as a clinical drug for treatment of anemia resulted from chronic kidney fail?ure. However, its short biological half-life makes frequent administration, which limits its wide clinical utility since the tough burden and pain on patients. Therefore, the development of EPO derivatives with good efficacy, less adverse reaction and long duration has been a hot spot in the field during several decades. There are currently many different variants of EPO derivatives including erythropoiesis stimulating agents (ESAs) on the market. This article aims to summarize the recent re?search progress in the development of erythropoietin derivatives, specially focusing on EPO mimetic peptides (EMP).

Papel protector de las lipoproteínas de alta densidad en sepsis: aspectos básicos e implicancias clínicas / Protective role of high density lipoproteins in sepsis: basic issues and clinical implications

High density lipoproteins (HDL) are responsible of reverse cholesterol transport and play an important antiatherogenic role. In recent years, several studies suggest that HDL have additional functions, including a possible anti-inflammatory activity in infectious conditions. Furthermore, available evidence indicates that the presence of lipopolysaccharide (LPS) within the circulation during infectious states induced by gram-negative bacteria may be involved in the decrease in HDL cholesterol levels and changes in lipoprotein composition, which have been associated with a higher mortality due to sepsis in animal models and in humans. In this article, we review this subject and also discuss possible mechanisms that explain the positive impact achieved by native HDL, reconstituted HDL, or HDL apolipoprotein peptides on the inflammatory response and mortality in models of endotoxemia. In this regard, it has been proposed that one of the mechanisms by which HDL protect against sepsis may be mediated by its binding ability and/or neutralizing capacity on LPS, avoiding an excessive response of the immune system. Thus, increasing blood levels of HDL and/or parenteral HDL administration may represent a new anti-inflammatory tool for managing septic states in humans.

Las lipoproteínas de alta densidad (HDL) son responsables del transporte reverso de colesterol y ejercen un importante papel anti-aterogénico. En los últimos años, diversos estudios indican que las HDL también tendrían otras funciones críticas, incluyendo una posible actividad anti-inflamatoria durante estados infecciosos. Además, la evidencia disponible sugiere que la presencia de lipopolisacárido (LPS) en la circulación durante estados infecciosos inducidos por bacterias gramnegativas podría estar involucrado en la disminución del colesterol HDL y los cambios en composición de esta clase lipoproteínas, lo cual se asociaría con una mayor tasa de mortalidad por sepsis en modelos animales y en humanos. En este trabajo, se revisan los antecedentes mencionados y además se discuten posibles mecanismos que explican la disminución de la respuesta inflamatoria y de la mortalidad que se logran en modelos de endotoxemia tratados con HDL o preparaciones similares. En este sentido, se ha propuesto que uno de los mecanismos protectores de las HDL estaría mediado por su capacidad de unión y/o neutralización del LPS, evitando una respuesta exacerbada del sistema inmune. De esta manera, el aumento de los niveles sanguíneos de HDL y/o su administración parenteral podrían constituir nuevas herramientas anti-inflamatorias para el manejo de estados sépticos en humanos.

Bio-mimetic drug delivery systems designed to help the senior population reconstruct melatonin plasma profiles similar to those of the healthy younger population

The secretion of melatonin (MT) is obviously different in the younger and the senior sectors of the population, and the maximum plasma concentration of seniors is only half of that in the younger population group. If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system (DDS), an improved therapeutic effect and reduced side effects can be expected. Based upon this hypothesis, the pharmacokinetic parameters of MT, namely, the absorption rate constant (k a), the elimination rate constant (k e), and the ratio of absorption rate (F) to the apparent volume of distribution (V) were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population. The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system (DDS) to generate plasma MT profiles similar to the physiological level-time profiles. The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates, namely, 4.919 μg/h during 0-4 h (r=0.9992), and 11.097 μg/h during 4-12 h (r=0.9886), respectively. Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors, an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population. The high similarity between the experimental drug release profiles and the theoretical profiles (similarity factor f 2>50) and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles (r=0.9366, 0.9163, 0.9264) indicated that a prototype bio-mimetic drug delivery system of MT was established. The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0-4 h and 4-12 h, namely, 68.8 and 57.3 for the first batch (Batch No. 20131031), 76.7 and 50.2 for the second batch (Batch No. 20131101), and 73.7 and 51.1 for the third batch (Batch No. 20131126), respectively. The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366 (Batch No. 20131031), 0.9163 (Batch No. 20131101), 0.9264 (Batch No. 20131126), respectively. Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings, it is impossible to test the bio-mimetic DDS in animals directly. Therefore, the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test. In this research, a bio-mimetic DDS for replacement of MT was designed with in silico evaluation.

The effect and mechanism of an apolipoprotein E mimetic peptide ApoE23 on plasma lipopolysaccharide levels in the septic mice / 中华急诊医学杂志

Objective To observe the effect of apolipoprotein E mimetic peptide (ApoE23) on lipopolysaccharide (LPS) levels in plasma and the regulatory role of ApoE23 on low density lipoprotein receptor (LDLR) on liver cells in the septic mice.Methods An ApoE mimetic peptide was designed and referred terminologically as ApoE23 in abbreviation.ApoE23 was synthesized by using solid phase synthesis assay and were refined by using high performance liquid chromatography (HPLC).The peptide was identified and confirmed by using electron spray ionization mass spectrometry and amino acid composition analysis.The C57BL mice infected with Salmonella typhimurium group B were treated with apoE23 injected into tail vein.The plasma LPS levels were measured by using immunoturbidimetry.The LDLR expression and level on liver cells were measured by real time PCR and western blot respectively.Results The plasma LPS levels significantly increased and the liver LDLR expression decreased in the septic mice.ApoE23 treatment markedly reduced the plasma LPS levels and redressed the LDLR down-expressions on liver cells both in mRNA and protein levels compared to the septic mice without ApoE23 treatment.Conclusions The reduction of LPS level after ApoE23 treatment may be associated with the modulation role of ApoE23 in LDLR expression on liver cells,and ApoE23 may be a potential agent against bacterial sepsis as well.One of possible mechanisms was most likely associated with effect of ApoE23 on LDLR expression.

Effects of Intensive Training for Mimetic Muscle on Idiopathic Facial Paralysis / 中国康复理论与实践

Objective To investigate the effects of intensive training for mimetic muscle on idiopathic facial paralysis. Methods 105 pa-tients with idiopathic facial paralysis were divided into control group (n=53) and treatment group (n=52). All the patients received the rou-tine treatment, including drugs, physical therapy, acupuncture and psychological support, while the treatment group was treated with inten-sive training for mimetic muscle in addition. Results 1 month after treatment, the muscle strength improved more in the treatment group than in the control group (P<0.01). The incidence of cure was 65.38%in the treatment group, more than 39.62%in the control group (P<0.01), as well the the total improvement of 96.15%and 83.02%respectively (P<0.05). Conclusion The intensive training for mimetic mus-cle can improve recovery of facial paralysis.