基于抗耐药性细菌感染的抗菌肽研究进展

随着抗生素的发现及滥用,耐药细菌感染已威胁到了人们的健康,现有抗生素已不能满足临床治疗的需求。因此,解决这一问题已迫在眉睫。本文针对耐药细菌的耐药机制及抗菌肽(antimicrobial peptides,AMPs)这一新型广谱抗菌药物的研究进展进行了综述。     

Role of Chrononutrition in the Antihypertensive Effects of Natural Bioactive Compounds

Hypertension (HTN) is one of the main cardiovascular risk factors and is considered a major public health problem. Numerous approaches have been developed to lower blood pressure (BP) in hypertensive patients, most of them involving pharmacological treatments. Within this context, natural bioactive compounds have emerged as a promising alternative to drugs in HTN prevention. This work reviews not only the mechanisms of BP regulation by these antihypertensive compounds, but also their efficacy depending on consumption time. Although a plethora of studies has investigated food-derived compounds, such as phenolic compounds or peptides and their impact on BP, only a few addressed the relevance of time consumption. However, it is known that BP and its main regulatory mechanisms show a 24-h oscillation. Moreover, evidence shows that phenolic compounds can interact with clock genes, which regulate the biological rhythm followed by many physiological processes. Therefore, further research might be carried out to completely elucidate the interactions along the time–nutrition–hypertension axis within the framework of chrononutrition.     

Chidamide stacked in magnetic polypyrrole nano-composites counter thermotolerance and metastasis for visualized cancer photothermal therapy

Photothermal therapy (PTT) has become one of the most promising therapies in cancer treatment as its noninvasiveness, high selectivity, and favorable compliance in clinic. However, tumor thermotolerance and distal metastasis reduce its efficacy, becoming the bottleneck of applying PTT in clinic. In this study, a chidamide-loaded magnetic polypyrrole nanocomposite (CMPP) has been fabricated as a visualized cancer photothermal agent (PTA) to counter tumor thermotolerance and metastasis. The efficacy of CMPP was characterized by in vitro and in vivo assays. As a result, this kind of magnetic polypyrrole nanocomposites were black spherical nanoparticles, possessing a favorable photothermal effect and the suitable particle size of 176.97 ± 1.45 nm with a chidamide loading rate of 12.92 ± 0.45%. Besides, comparing with PTT, CMPP exhibited significantly higher cytotoxicity and cellular apoptosis rate in two tumor cell lines (B16-F10 and HepG2). In vivo study, the mice showed obvious near-infrared (NIR) and magnetic resonance imaging (MRI) dual-modal imaging at tumor sites and sentinel lymph nodes (SLNs); on the other hand, magnetic targeting guided CMPP achieved a cure level on melanoma-bearing mice through preventing metastasis and thermotolerance. Overall, with high loading efficiency of chidamide and strong magnetic targeting to tumor sites and SLNs, CMPP could significantly raise efficiency of PTT by targeting tumor thermotolerance and metastasis, and this strategy may be exploited therapeutically to upgrade PTT with MPP as one of appropriate carriers for histone deacetylase inhibitors (HDACis).     

三磷酸腺苷脂质体的研究进展

本文综述了近年来三磷酸腺苷(ATP)脂质体的研究进展.脂质体作为新载体可以提高ATP在体内的稳定性,并且能靶向于缺血的心肌和缺血的大脑,用于器官移植中能提高冷冻贮存器官的能级状态,提高移植的成活率,故制备稳定的ATP脂质体具有重要的意义.本文还综述了ATP脂质体的制备方法,探讨如何进一步提高脂质体的包裹率和靶向性,以用于临床.     

Angiopep-2与转铁蛋白共修饰脂质体跨血脑屏障的研究

【摘要】目的：构建angiopep-2与转铁蛋白共修饰脂质体,并对其理化性质和跨血脑屏障能力进行评价。方法 采用薄膜分散法制备转铁蛋白（TF）与angiopep-2共修饰载脂质体（ANG/TF-LPs）,考察其粒径,电位,血清稳定性等理化特征。通过定量细胞摄取实验考察脑内皮bEnd.3细胞对ANG/TF-LPs的摄取效率。构建血脑屏障体外模型,考察不同脂质体的跨血脑屏障能力。结果 所制备的ANG/TF-LPs粒径为93±13.5 nm, Zeta 电位为7.55±1.85 mV。在24 h内具有良好的血清稳定性。体外细胞摄取实验表明,bEnd.3细胞对ANG/TF-LPs的摄取效率分别是TF-LPs、ANG-LPs和LPs的2.9倍、2.4倍和4.8倍,差异具有统计学意义（P<0.01）;ANG/TF-LPs的跨血脑屏障效率分别是TF-LPs、ANG-LPs和LPs的3.1倍、2.9倍和6.8倍,差异具有统计学意义（P<0.01）。结论 ANG/TF-LPs制备工艺简单,经过angiopep-2与转铁蛋白修饰后,脂质体的跨血脑屏障能力显著增强,是一种潜在高效的脑部靶向给药系统。     

Genetic disruption of USP9X sensitizes colorectal cancer cells to 5-fluorouracil

The X-linked deubiquitinase USP9X affects the stability and activity of numerous regulatory proteins that influence cell survival. Recent studies suggest that decreased USP9X expression can confer a selective advantage onto developing cancer cells and thereby promotes disease progression. To examine the effect of USP9X on the cellular responses to anticancer therapies, we derived cancer cell lines in which the USP9X locus was disrupted by homologous recombination. The resulting USP9X-deficient cancer cells exhibited increased activation of apoptotic pathways and markedly decreased clonogenic survival in response to 5-fluorouracil, a chemotherapeutic drug that is widely used for treatment of gastrointestinal malignancies. These unexpected results suggest that cancers with low USP9X expression might be specifically sensitized to some conventional therapeutic agents.     

Immune Response to Dietary Proteins,Gliadin and Cerebellar Peptides in Children with Autism

Abstract

The mechanisms behind autoimmune reaction to nervous system antigens in autism are not understood. We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously. For examining cross-reaction between dietary proteins and cerebellar antigens, antibodies were prepared in rabbits, and binding of rabbit anti-gliadin, anti-cerebellar peptides, anti-MBP, anti-milk, anti-egg, anti-soy and anti-corn to either gliadin- or cerebellar-antigen-coated wells was measured. In comparison to anti-gliadin peptide binding to gliadin peptide at 100%, the reaction of anti-cerebellar peptide to gliadin peptide was 22%, whereas the binding of anti-myelin basic protein (MBP), anti-milk, anti-egg and anti-soy to gliadin was less than 10%. Further examination of rabbit anti-gliadin (EQVPLVQQ) and anti-cerebellar (EDVPLLED) 8 amino acid (AA) peptides with human serum albumin (HSA) and an unrelated peptide showed no binding, but the reaction of these antibodies with both the cerebellar and gliadin peptides was greater than 60%. This cross-reaction was further confirmed by DOT-immunoblot and inhibition studies. We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.     

Gemcitabine Hydrochloride-Loaded Functionalised Carbon Nanotubes as Potential Carriers for Tumour Targeting

The objective of the present work was to formulate gemcitabine hydrochloride loaded functionalised carbon nanotubes to achieve tumour targeted drug release and thereby reducing gemcitabine hydrochloride toxicity. Multiwalled carbon nanotubes were functionalised using 1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000. Optimised ratio 1:2 of carbon nanotubes:1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000 was taken for loading of gemcitabine hydrochloride. The formulation was evaluated for different parameters. The results showed that maximum drug loading efficiency achieved was 41.59% with an average particle size of 188.7 nm and zeta potential of −10−1 mV. Scanning electron microscopy and transmission electron microscopy images confirmed the tubular structure of the formulation. The carbon nanotubes were able to release gemcitabine hydrochloride faster in acidic pH than at neutral pH indicating its potential for tumour targeting. Gemcitabine hydrochloride release from carbon nanotubes was found to follow Korsmeyer-Peppas kinetic model with non-Fickian diffusion pattern. Cytotoxic activity of formulation on A549 cells was found to be higher in comparison to free gemcitabine hydrochloride. Stability studies indicated that lyophilised samples of the formulation were more stable for 3 months under refrigerated condition than at room temperature. Thus carbon nanotubes can be promising carrier for the anticancer drug gemcitabine hydrochloride.     

LPS interactions with immobilized and soluble antimicrobial peptides

Abstract

A promising approach in sepsis therapy is the use of peptides truncated from serum- and membrane-proteins with binding domains for LPS: antimicrobial peptides (AMPs). AMPs can be useful in combination with conventional antibiotics to increase killing and neutralize LPS. Although many AMPs show a high specificity towards bacterial membranes, they can also exhibit toxicity, i.e. non-specific membrane lysis, of mammalian cells such as erythrocytes and therefore, unsuitable as systemic drugs. A way to overcome this problem may be an extracorporeal therapy with immobilized peptides. This study will compare neutralization of LPS using different AMPs in solution and when immobilized on to solid phases. The peptides ability to neutralize LPS-induced cytokine release in whole blood will also be tested. The peptides are truncated derivates from the known AMPs LL-37, SC4, BPI, S3Δ and CEME. Two different methods were used to immobilize peptides, biomolecular interaction analysis, and Pierce SulfoLink Coupling Gel. To investigate LPS binding in solution the LAL test was used. After whole blood incubation with LPS and AMPs ELISA was used to measure TNFα, IL-1β and IL-6 production. The results suggest that immobilization of antimicrobial peptides does not inhibit their capacity to neutralize LPS, although there are differences between the peptides tested. Thus, peptides derived from LL-37 and CEME were more efficient both in LPS binding and neutralizing LPS-induced cytokine production.