地塞米松对大鼠肝脏Mrp2和AQP1表达的影响

【目的】探讨地塞米松（Dex）对Wistar大鼠肝胆系统多药耐药相关蛋白2（Mrp2）和水通道蛋白1（AQPt）的调节作用。【方法】20只Wistar大鼠随机分为空白对照组和Dex干预组，观测1h胆汁流量、直接胆红素（DBIL），用免疫组织化学的方法观测Mrp2和AQP1的表达。【结果】干预组较之对照组胆汁量增加（P〈0．05），血清DBIL明显下降（P〈0．01），胆汁DBIL差异无显著性（P〉0．05），Mrp2和AQP1免疫组化切片光密度值增加（P〈0．01）。【结论】Dex可增加大鼠肝胆系统Mrp2和AQP1的表达。血清DBIL下降，胆汁分泌量增加，与Mrp2和AQP1的表达相关。     

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.     

The peritoneal microcirculation in peritoneal dialysis.

This paper deals with the peritoneal microcirculation and with peritoneal exchange occurring in peritoneal dialysis (PD). The capillary wall is a major barrier to solute and water exchange across the peritoneal membrane. There is a bimodal size-selectivity of solute transport between blood and the peritoneal cavity, through pores of radius approximately 40-50 A as well as through a very low number of large pores of radius approximately 250 A. Furthermore, during glucose-induced osmosis during PD, nearly 40% of the total osmotic water flow occurs through molecular water channels, termed "aquaporin-1." This causes an inequality between 1 - sigma and the sieving coefficient for small solutes, which is a key feature of the "three-pore model" of peritoneal transport. The peritoneal interstitium, coupled in series with the capillary walls, markedly modifies small-solute transport and makes large-solute transport asymmetric. Thus, although severely restricted in the blood-to-peritoneal direction, the absorption of large solutes from the peritoneal cavity occurs at a high clearance rate ( approximately 1 mL/min), largely independent of molecular radius. True absorption of macromolecules to the blood via lymphatics, however, seems to be occurring at a rate of approximately 0.2 mL/min. Several controversial issues regarding transcapillary and transperitoneal exchange mechanisms are discussed in this paper.     

三七总皂甙对脑出血后大鼠脑水肿及水通道蛋白-4表达的影响

目的观察三七总皂甙对脑出血大鼠脑水肿形成及水通道蛋白-4(AQP4)表达的影响。方法Wistar大鼠198只随机分为A、B、C 3个部分,分别检测脑含水量、AQP4蛋白和AQP4 mRNA,每部分又随机分为假手术组,模型组,治疗组,采用干湿重法、免疫组织化学染色、逆转录聚合酶链反应技术分别测定脑含水量、AQP4蛋白和AQP4 mRNA的表达。结果治疗组和模型组12 h之后脑含水量增加(P<0.05),1天时脑含水量明显增加(P<0.01),3天时脑含水量达到高峰并持续到5天,在相同的时间点,治疗组脑含水量比模型组明显少(P<0.05);模型组和治疗组12 h之后AQP4蛋白和AQP4 mRNA表达水平增加(P<0.05),1天时明显升高(P<0.01),3天达到高峰持续至5天,以后逐渐下降,与模型组比较,治疗组大鼠在各时间点AQP4蛋白、AQP4 mRNA均在低水平表达(P<0.05),1-5天表达水平明显下降(P<0.01)。结论三七总皂甙可能通过抑制AQP4的表达减轻脑出血后脑水肿的形成。     

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.     

Highly permeable artificial water channels that can self-assemble into two-dimensional arrays

Bioinspired artificial water channels aim to combine the high permeability and selectivity of biological aquaporin (AQP) water channels with chemical stability. Here, we carefully characterized a class of artificial water channels, peptide-appended pillar[5]arenes (PAPs). The average single-channel osmotic water permeability for PAPs is 1.0(±0.3) × 10⁻¹⁴ cm³/s or 3.5(±1.0) × 10⁸ water molecules per s, which is in the range of AQPs (3.4∼40.3 × 10⁸ water molecules per s) and their current synthetic analogs, carbon nanotubes (CNTs, 9.0 × 10⁸ water molecules per s). This permeability is an order of magnitude higher than first-generation artificial water channels (20 to ∼10⁷ water molecules per s). Furthermore, within lipid bilayers, PAP channels can self-assemble into 2D arrays. Relevant to permeable membrane design, the pore density of PAP channel arrays (∼2.6 × 10⁵ pores per μm²) is two orders of magnitude higher than that of CNT membranes (0.1∼2.5 × 10³ pores per μm²). PAP channels thus combine the advantages of biological channels and CNTs and improve upon them through their relatively simple synthesis, chemical stability, and propensity to form arrays.The discovery of the high water and gas permeability of aquaporins (AQPs) and the development of artificial analogs, carbon nanotubes (CNTs), have led to an explosion in studies aimed at incorporating such channels into materials and devices for applications that use their unique transport properties (1–9). Areas of application include liquid and gas separations (10–13), drug delivery and screening (14), DNA recognition (15), and sensors (16). CNTs are promising channels because they conduct water and gas three to four orders of magnitude faster than predicted by conventional Hagen–Poiseuille flow theory (11). However, their use in large-scale applications has been hampered by difficulties in producing CNTs with subnanometer pore diameters and fabricating membranes in which the CNTs are vertically aligned (4). AQPs also efficiently conduct water across membranes (∼3 billion molecules per second) (17) and are therefore being studied intensively for their use in biomimetic membranes for water purification and other applications (1, 2, 18). The large-scale applications of AQPs is complicated by the high cost of membrane protein production, their low stability, and challenges in membrane fabrication (1).Artificial water channels, bioinspired analogs of AQPs created using synthetic chemistry (19), ideally have a structure that forms a water-permeable channel in the center and an outer surface that is compatible with a lipid membrane environment (1). Interest in artificial water channels has grown in recent years, following decades of research and focus on synthetic ion channels (19). However, two fundamental questions remain: (i) Can artificial channels approach the permeability and selectivity of AQP water channels? (ii) How can such artificial channels be packaged into materials with morphologies suitable for engineering applications?Because of the challenges in accurately replicating the functional elements of channel proteins, the water permeability and selectivity of first-generation artificial water channels were far below those of AQPs (SI Appendix, Table S1) (20–25). In some cases, the conduction rate for water was much lower than that of AQPs as a result of excess hydrogen bonds being formed between the water molecules and oxygen atoms lining the channel (20). The low water permeability that was measured for first-generation water channels also highlights the experimental challenge of accurately characterizing water flow through low-permeability water channels. Traditionally, a liposome-based technique has been used to measure water conduction, in which the response to an osmotic gradient is followed by measuring changes in light scattering (26, 27) or fluorescence (28). The measured rates are then converted to permeability values. These measurements suffer from a high background signal due to water diffusion through the lipid bilayer, which, in some cases, can be higher than water conduction through the inserted channels, making it challenging to resolve the permeability contributed by the channels (29). Thus, there is a critical need for a method to accurately measure single-channel permeability of artificial water channels to allow for accurate comparison with those of biological water channels. Furthermore, first-generation artificial water channels were designed with a focus on demonstrating water conduction and one-dimensional assembly into tubular structures (20–24), but how the channels could be assembled into materials suitable for use in engineering applications was not explored. To derive the most advantage from their fast and selective transport properties, artificial water channels are ideally vertically aligned and densely packed in a flat membrane. These features have been long desired but remain a challenge for CNT-based systems (4).Here we introduce peptide-appended pillar[5]arene (PAP; Fig. 1) (30) as an excellent architecture for artificial water channels, and we present data for their single-channel permeability and self-assembly properties. Nonpeptide pillar[5]arene derivatives were among first-generation artificial water channels (1, 23). Pillar[5]arene derivatives, including the one used in this study, have a pore of ∼5 Å in diameter and are excellent templates for functionalization into tubular structures (31–34). However, the permeability of hydrazide-appended pillar[5]arene channels was low (∼6 orders of magnitude lower than that of AQPs; SI Appendix, Table S1). We addressed the challenges of accurately measuring single-channel water permeability and improving the water conduction rate over first-generation artificial water channels by using both experimental and simulation approaches. The presented PAP channel contains more hydrophobic regions (30) compared with its predecessor channel (23), which improves both its water permeability and its ability to insert into membranes. To determine single-channel permeability of PAPs, we combined stopped-flow light-scattering measurements of lipid vesicles containing PAPs with fluorescence correlation spectroscopy (FCS) (35, 36). Stopped-flow experiments allow the kinetics of vesicle swelling or shrinking to be followed with millisecond resolution and water permeability to be calculated, whereas FCS makes it possible to count the number of channels per vesicle (36, 37). The combination of the two techniques allows molecular characterization of channel properties with high resolution and demonstrates that PAP channels have a water permeability close to those of AQPs and CNTs. The experimental results were corroborated by molecular dynamics (MD) simulations, which also provided additional insights into orientation and aggregation of the channels in lipid membranes. Finally, as a first step toward engineering applications such as liquid and gas separations, we were able to assemble PAP channels into highly packed planar membranes, and we experimentally confirmed that the channels form 2D arrays in these membranes.Open in a separate windowFig. 1.Structure of the peptide-appended pillar[5]arene (PAP) channel. (A) The PAP channel (C₃₂₅H₃₂₀N₃₀O₆₀) forms a pentameric tubular structure through intramolecular hydrogen bonding between adjacent alternating d-l-d phenylalanine chains (d-Phe-l-Phe-d-Phe-COOH). (B) Molecular modeling (Gaussian09, semiempirical, PM6) of the PAP channel shows that the benzyl rings of the phenylalanine side chains extend outward from the channel walls (C, purple; H, white; O, red; N, blue). (C and D) MD simulation of the PAP channel in a POPC bilayer revealed its interactions with the surrounding lipids. The five chain-like units of the channel are colored purple, blue, ochre, green, and violet, with hydrogen atoms omitted. In C, the POPC lipids are represented by thin tan lines; in D, water is shown as red (oxygen) and white (hydrogen) van der Waals spheres.     

Impaired aquaporins expression in the gastrointestinal tract of rat after mercury exposure

The main route of exposure to mercury in humans is through the diet. Consequently, the gastrointestinal mucosa is exposed to the mercurial forms, where they cause intestinal fluid accumulation, mucosal injuries and diarrhea. The relationship between inorganic mercury (HgCl₂) and methylmercury (CH₃HgCl) exposure and water movement in the gastrointestinal tract is still unexplored. The leading role of aquaporins (AQPs) in the rapid bidirectional movement of fluid in the gastrointestinal tract of mammals is well established. The present study evaluates the effect of HgCl₂ and CH₃HgCl exposure on AQP expression in different portions of the gastrointestinal tract of rats treated by gavage (5 mg kg^–1 of mercury species, single dose, 4 days). The results show that mercury species reduce mRNA and protein levels of AQPs in different parts of the gastrointestinal tract. In the stomach, treated rats show a significant reduction of expression of AQP3 (80–90% for mRNA and 50% for protein) and AQP4 (95–99% for mRNA and 20–40% for protein). In the small and large intestine, treated rats experience a significant reduction of AQP3 and AQP7 expression. Protein contents of both AQPs are reduced in similar proportions in jejunum (AQP3: 40–50%; AQP7: 45–50%) and colon (AQP3: 35–40%; AQP7: 45–60%), regardless of the treatment. Our results indicate that some AQPs are downregulated in the rat gastrointestinal tract by mercury exposure, suggesting a possible role of AQPs in the development of mercury gastrointestinal symptoms. Copyright © 2015 John Wiley & Sons, Ltd.     

<Emphasis Type="Italic">In vitro</Emphasis> study of the role of lenticular epithelial calcium channels and aquaporins in the development of cataract

The role of calcium and water channels (aquaporins) in the pathogenesis of cataract was studied in vitro. Aquaporin blockade caused opacity of the lens sooner than changes in calcium ion concentration in culture medium. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 2, pp. 144–147, February, 2008     

水通道蛋白抑制剂和分子靶向治疗的研究进展

水通道蛋白是细胞膜转运水分子的特异性通道蛋白,在维持机体水平衡中发挥重要作用。研究发现水通道蛋白广泛分布在人体各组织器官,其表达异常与一系列水平衡紊乱导致的疾病密切相关。近年来针对水通道蛋白的基础研究、水通道蛋白特异性抑制剂和水通道蛋白分子靶向治疗等取得了诸多进展,本文对此进行综述。