多胺在动脉粥样硬化发生发展过程中的变化

目的：探讨动脉粥样硬化的发病机制。方法：采用雄性日本鹌鹑喂饲高胆固醇膳食,造成动脉粥样硬化动物模型,动脉观察主动脉壁的中内膜的多胺变化。结果：血浆胆固醇和分类胆固醇提示高脂血症,结合病理切片,说明本实验动脉粥样硬化模型可靠。结论：1．多胺对动脉粥样硬化的发生起着重要作用;2．多胺在动脉粥样硬化发生（病理标准）前升高,后又依次降低的特殊现象。     

Antitumor conjugates with polyamine vectors and their molecular mechanisms

Importance of the field: A polyamine conjugate is a special polyamine derivative composed of polyamine vectors appended directly or by a linker to a cargo with specific biological functions. In recent years, extensive researches have emphasized the fact that polyamine conjugates acting as promising antitumor candidates are becoming increasingly important in the polyamine field.

Areas covered in this review: Two key subjects are illustrated in this review. First, various drug-polyamine conjugates and relevant structure–activity relationships are discussed with a focus on the molecular recognition of polyamine transport system (PTS). Second, the design of polyamine conjugates is following a rational mechanism-based strategy. Therefore, it is critically important to understand the intrinsic properties of PTS on the cell membrane, enhanced pharmacological effects of polyamine vector on cellular components, and resulting comprehensive signaling networks.

What the reader will gain: A general design strategy of polyamine conjugates as well as recent progress in both fundamental mechanism studies and preclinical therapies are provided for the readers.

Take home message: The multiple functions of polyamine moieties in objective conjugates furnish broad development space for more efficacious antitumor agents.     

抗咯萘啶的伯氏疟原虫感染红细胞多胺量的测定

目的：了解疟原虫的多胺代谢与咯萘啶（ＰＮＤ）抗药性的关系。方法：感染伯氏疟原虫ＡＮＫＡ株（ＰＳ）和由该株培育的中抗ＰＮＤ品系（ＰＲＡ）及高抗ＰＮＤ品系（ＰＲＢ）的昆明株小鼠于腹腔接种（ｉｐ）后ｄ７取血，经薄层层析后用荧光分光光度法测定正常ＲＢＣ、ＰＳ、ＰＲＡ和ＰＲＢ感染ＲＢＣ的丁二胺（ＰＴＣ）、精脒（ＳＰＤ）和精胺（ＳＰＭ）量。另有感染ＰＳ和ＰＲＢ的小鼠于ｉｐ后ｄ６分别１次灌胃（ｉｇ）ＰＮＤ５ｍｇ／ｋｇ和１０ｍｇ／ｋｇ，ｄ７取血，按上述方法测定给药后感染ＲＢＣ的多胺量，并与不给药组比较。结果：ＰＳ感染ＲＢＣ的多胺量均明显高于未感染疟原虫的正常ＲＢＣ，而感染ＰＲＡ和ＰＲＢ的ＲＢＣ多胺量又显著高于ＰＳ感染ＲＢＣ，且多胺量的增高与抗性程度有关。经ＰＮＤ治疗后ＰＳ感染ＲＢＣ的ＳＰＤ和ＳＰＭ较未治疗组显著下降，而ＰＲＢ感染ＲＢＣ则未见明显变化。结论：伯氏疟原虫对ＰＮＤ的抗药性与其多胺代谢有关。     

ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress

Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death. Moreover, ATP13A2 knockdown induced an ATF4-CHOP-dependent stress response following rotenone exposure. MitoROS and ATF4-CHOP were blocked by MitoTEMPO, a mitochondrial antioxidant, suggesting that the impact of ATP13A2 on MitoROS may relate to the antioxidant properties of spermine. Pharmacological inhibition of intracellular polyamine synthesis with α-difluoromethylornithine (DFMO) also increased MitoROS and ATF4 when ATP13A2 was deficient. The polyamine transport activity of ATP13A2 was required for lowering rotenone/DFMO-induced MitoROS, whereas exogenous spermine quenched rotenone-induced MitoROS via ATP13A2. Interestingly, fluorescently labeled spermine uptake in the mitochondria dropped as a consequence of ATP13A2 transport deficiency. Our cellular observations were recapitulated in vivo, in a Caenorhabditis elegans strain deficient in the ATP13A2 ortholog catp-6. These animals exhibited a basal elevated MitoROS level, mitochondrial dysfunction, and enhanced stress response regulated by atfs-1, the C. elegans ortholog of ATF4, causing hypersensitivity to rotenone, which was reversible with MitoTEMPO. Together, our study reveals a conserved cell protective pathway that counters mitochondrial oxidative stress via ATP13A2-mediated lysosomal spermine export.

Loss-of-function mutations in ATP13A2 (PARK9) are causative for a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome (KRS, a juvenile onset parkinsonism with dementia) (1), early-onset Parkinson’s disease (PD) (2, 3), hereditary spastic paraplegia (HSP) (4), neuronal ceroid lipofuscinosis (5), and amyotrophic lateral sclerosis (6), which are commonly hallmarked by lysosomal and mitochondrial dysfunction (4, 6, 7). Also, ATP13A2 deficiency causes lysosomal and mitochondrial impairment in various models, as evidenced by decreased lysosomal functionality (8, 9), reduced mitochondrial clearance capacity (8–10), mitochondrial fragmentation, mitochondrial DNA damage, and increased oxygen consumption (11, 12).We recently discovered that ATP13A2 transports the polyamines spermidine and spermine from the late endo/lysosome to the cytosol (9). Polyamines are ubiquitous polycationic aliphatic amines that stabilize nucleic acids, influence protein folding, regulate ion channels, and modulate cell proliferation and differentiation (13–15). We found that the late endo-lysosomal transporter ATP13A2 strongly contributes to the total cellular polyamine content via a two-step process: Firstly, polyamines enter the cell via endocytosis and subsequently, polyamines are transported by ATP13A2 into the cytosol (9). This process complements polyamine biosynthesis via the ornithine decarboxylase (ODC) pathway (9). Importantly, ATP13A2’s polyamine transport function is crucial for its neuroprotective effect, since it prevents lysosomal polyamine accumulation and subsequent lysosomal rupture, while improving lysosomal health and functionality (9). Moreover, when activated by its two regulatory lipids—phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] and phosphatidic acid (PA)—ATP13A2 exerts a cell protective effect against the mitochondrial neurotoxin rotenone (16), an environmental risk factor for PD (17). Rotenone is a mitochondrial complex I inhibitor, which leads to high levels of reactive oxygen species (ROS), promoting protein aggregation and damaging organelles. However, how ATP13A2’s polyamine transport function exerts a cell protective effect against rotenone, or other mitochondrial neurotoxins, is not yet clear.Interestingly, the transported substrates spermine and spermidine reduce oxidative stress (14, 15). Spermine is a potent free radical scavenger (18) and a biologically important antioxidant (19–23). We therefore hypothesize that ATP13A2-mediated polyamine transport may counteract oxidative stress (16, 24) and preserve mitochondrial health (11, 12). Here, we demonstrate in complementary human cell models and Caenorhabditis elegans that lysosomal polyamine export by ATP13A2 effectively lowers ROS levels and promotes mitochondrial health and functionality, pointing to a lysosomal-dependent cell protective pathway that may be implicated in ATP13A2-related neurodegenerative disorders.     

多胺对细菌生物膜作用的多样性

生物膜的形成和分散受多种因素调控,阻断生物膜的形成及促进生物膜的解离分散是目前的研究热点和前沿方向。近年来的研究表明,多胺这一在原核和真核生物中广泛存在的物质同样在细菌生物膜的形成和分散过程中起到了非常重要的作用,本文就多胺对细菌生物膜相关作用的研究作一综述。     

自制多聚胺阳离子脂质体转染效率及细胞毒性的评价

目的: 评估制备的多聚胺阳离子脂质体转染哺乳动物细胞的转染效率及细胞毒性. 方法: 多聚胺阳离子脂质TC-Chol与中性磷脂DOPE以3: 1摩尔比,制备多聚胺阳离子脂质体,通过转染以增强型绿色荧光蛋白为报告基因的质粒PIRES2-EGFP入HeLa细胞, Hep2细胞,倒置荧光显微镜下检测转染细胞的报告基因表达,通过MTT法,检测细胞存活分数,并以Lipofectamine2000为对照,评价制备阳离子脂质体转染效率及细胞毒性. 结果: 多聚胺阳离子脂质体转染效率略低于Lipofectamine 2000,但细胞毒性较低,为一种相对高效低毒的阳离子脂质体. 结论: 多聚胺阳离子脂质体为一种相对高效低毒的阳离子脂质体,在基因转染和基因治疗方面具有较广阔的前景.     

多聚胺阳离子脂质体转染效率及细胞毒性的评价

目的评估四种多聚胺阳离子脂质体的转染效率及细胞毒性,筛选高效低毒的阳离子脂质体。方法多聚胺阳离子脂质TC-Chol、DC-Chol与中性磷脂DOPE分别以1：1、3：1摩尔比制备多聚胺阳离子脂质体,转染以增强型绿色荧光蛋白为报告基因的质粒PIRES2-EGFP入Hela细胞、Hep2细胞,倒置荧光显微镜下检测转染细胞的报告基因表达,筛选出高效的阳离子脂质体,通过MTT法检测转染细胞毒性,从而筛选相对高效低毒的阳离子脂质体。结果所制备的多聚胺阳离子脂质体在透射电镜下呈圆形、椭圆形囊泡样结构,少数呈管状、不规则状,粒径50-200nm,可将质粒PIRES2-EGFP有效转染入Hela细胞、Hep2细胞,其中多聚胺阳离子脂质TC-Chol与DOPE以3：1摩尔比制备的多聚胺阳离子脂质体是一种相对高效低毒的阳离子脂质体,转染效率39．5％～42．1％。结论多聚胺阳离子脂质TC-Chol、DC-Chol与中性磷脂DOPE以一定的摩尔比可制备高效低毒的多聚胺阳离子脂质体,其转染效率和细胞毒性与阳离子脂质的结构和中性磷脂DOPE的比例有关,在基因转染和基因治疗方面具有较广阔的应用前景。     

多胺代谢在调控肿瘤血管生成中作用机制的研究进展

摘　要：多胺（PA）是普遍存在于动植物所有组织和细胞类型中的脂族聚阳离子,与肿瘤的血管生成密切相关。该文 就多胺代谢与肿瘤血管生成的关系及机制的研究进展进行综述,以期为靶向多胺代谢的临床抗肿瘤血管生成治疗提供 新的理论依据。     

The Impact of Polyamine Analogues on the Blood Pressure of Normotensive and Hypertensive Rats

The impact of the antineoplastic polyamine analogues N¹N¹⁴-diethylhomospermine (DEHSPM) and N¹N¹¹-diethylnorspermine (DENSPM) on the blood pressure and heart rate of normotensive and hypertensive rats are described. DEHSPM was administered to both normotensive and spontaneously hypertensive rats (SHR), while the DENSPM analogue was given only to the normotensive animals. The intravenous administration of DEHSPM a t doses of 5 or 10 mg/kg resulted in a profound and long-lasting drop in the test animals' blood pressure, with no appreciable change in their heart rate. This was true for both the normotensive and the hypertensive animals. When administered at equivalent molar dosages, DENSPM was one fifth as effective as DEHSPM at reducing blood pressure. The impact of NG-nitro-L-arginine- methyl ester (L-NAME) and L-arginine on the analogues' activity is consistent with the involvement of nitric oxide.