Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment

Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual-functionalized cationic liposome containing a synthetic cationic lipid, 1,5-dioctadecyl-N-histidyl-l-glutamate (HG2C₁₈) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C₁₈ lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment.     

传统中医理论指导下的老年人养生

《黄帝内经》确立了老年人养生的指导思想,奠定了中医养生学的基础,《内经》中关于老年人养生的理论特征、养生原则、养生方法都具有现实意义。以未病先防为指导,明确慎起居、勤锻炼、适饮食、调情志为具体的养生方法,《黄帝内经》的养生理论重视保养先天真气,主张老年人养生应当顺其自然,体现了自然而然的养生理念。     

基于正虚机制观察益气健脾法治疗慢性乙型肝炎肝衰竭的临床疗效

目的基于正虚机制观察益气健脾法治疗慢乙肝肝衰竭的临床疗效,探讨补虚法在慢性肝衰竭治疗中的作用。方法采用随机、对照方法,将50例慢乙肝肝衰竭患者随机平均分为两组,对照组给予常规内科综合治疗;治疗组在内科综合治疗基础上予以益气健脾为主的中药煎剂口服。观察两组治疗2周时的临床转归、TBil与PTA的改善程度及MELD评分变化。结果治疗组有效率72.00%高于对照组的40.00%;治疗组TBil,PTA及MELD评分改善程度均优于对照组。结论在内科综合治疗的基础上,基于正虚机制以益气健脾法治疗慢乙肝肝衰竭,能够明显提高临床疗效。     

Role of nitric oxide in the anticonvulsive effect of progesterone

Described here is an investigation of the potential interaction of the nitric oxide signaling pathway with the anticonvulsant effects of progesterone. In ovariectomized Swiss mice, the threshold for seizures induced by intravenous infusion of pentylenetetrazole was determined after treatment with progesterone (25, 50, or 75 mg/kg, given subcutaneously 6 h before seizure testing) or vehicle. Progesterone induced significant anticonvulsive activity at moderate (50 mg/kg) and high (75 mg/kg) doses. This effect of progesterone was abolished by the NO precursor compound l-arginine (200 mg/kg). Moreover, when subeffective doses of progesterone (25 mg/kg) and the NO synthase inhibitor N^ω-nitro-l-arginine methyl ester (10 mg/kg) were injected, a strong anticonvulsant effect was observed. These findings suggest a potential role for NO signaling as an anticonvulsant target in females.     

针灸适应症的研究现状和发展趋势

To discuss the dominant diseases of acupuncture and moxibustion and their trend in development. At present, the concepts of acupuncture and moxibustion disease spectrum include efficacy-based graded disease spectrum of acupuncture and moxibustion and evidence-based graded disease spectrum of acupuncture and moxibustion. Hence, the ranges of dominant diseases are various in terms of the different concepts. Regarding the efficacy-based graded disease spectrum, 81 dominant diseases are included. In accordance with the principle of disease spectrum of evidence-based acupuncture and moxibustion, the articles of systematic reviews and meta-analysis of acupuncture and moxibustion published in Chinese medical journals were retrieved, and thus 68 dominant diseases of acupuncture and moxibustion were collected. In view of the retrieval result and the effect characteristics of acupuncture and moxibustion, the authors believe that the following 4 aspects should be involved in the development of the dominant diseases of acupuncture and moxibustion, named (1) painful diseases, (2) neurological disorders, (3) mental, cognitive and affective diseases and (4) immune-endocrine disorders.     

Structural characterization,in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine

Objective: The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products.Methods: The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrol...     

Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4′-(9-acridinylamino)-methanesulphon-o-anisidide (o-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4-acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [¹⁴C]CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by o-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC ctytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a ‘cleavable complex’ in which the DNA is covalently linked to the enzyme.