Brain and other natriuretic peptides: molecular aspects

Natriuretic peptides have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular disease. The family contains of three major peptides-ANP, BNP, CNP-that participate in cardiovascular and cardiorenal homeostasis. Each of these natriuretic peptides binds differentially to specific receptors that signal through different mechanisms. They are cleared enzymatically by neutral endopeptidase as well as by receptor-mediated endocytosis. Because of its fast induction and specific expression in overt heart failure, BNP seems the most promising natriuretic peptide. It is predominantly synthesized in the cardiac ventricles, released as pre-proBNP and then enzymatically cleaved to BNP and the N-terminal portion of BNP(NT-proBNP). Blood measurements of BNP and NT-proBNP have been shown to identify patients with LV dysfunction. This review focuses on the physiology of natriuretic peptides as a group and brain natriuretic peptide in more detail, its structure and regulation as well as its effects at the cellular level.     

肉孢子虫及其它成囊球虫的分子生物学研究进展

随着分子生物学及基因诊断学的理论和技术在广度和深度的发展 ,使得人们应用这一工具对生物界许多方面进行更为深入的研究成为可能。肉孢子虫 ( Sarcocystis)及其它成囊球虫 ( cyst- formingCoccidia)的研究也不例外。本文将现代分子生物学及基因诊断技术应用于肉孢子虫及其成囊球虫病的诊断及研究进展作一综述。基因序列测定、分析1　亲缘关系的确定过去的几十年 ,人们通过生活史型 (单宿主或多宿主 ) ,虫体在中间宿主中的成囊部位 ,在中间宿主和终末宿主中的各期形态及增殖形式 ,以及用电镜结构定种方法进行分类。但种间的亲缘关系仅用这…     

Low molecular weight IgM in rheumatoid arthritis and other rheumatic diseases

Low molecular weight (LMW) IgM was measured in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and other rheumatic diseases. High levels were seen in RA, particularly in rheumatoid vasculitis and Felty's syndrome, and significant correlations occurred between LMW IgM and the rheumatoid factor (RF) level and other indices that reflected active or severe disease. LMW IgM-RF, measured by radio-immunoassay in those column fractions containing LMW IgM, correlated significantly with LMW IgM (P < 0.005); preliminary experiments suggested that in some sera, a considerable proportion of the LMW IgM consisted of LMW IgM-RF. We conclude that LMW IgM and LMW IgM-RF may have important implications in the immunopathogenesis of RA and other rheumatic diseases.     

Microsatellite instability and other molecular abnormalities in childhood acute lymphoblastic leukaemia

Microsatellite instability (MSI) has been considered to represent the defect of DNA mismatch repair systems and has been implicated in the tumourigenesis of several human malignancies. To investigate the possible presence of microsatellite instability in childhood acute lymphoblastic leukaemia (ALL), we examined 48 primary ALL samples. Instability was determined at 85 different microsatellite loci localized to 12 different chromosome arms.   Microsatellite instability was detected in five (10%) samples. Interestingly, the instability was found at chromosomal regions associated with frequent alterations. Two samples had instability at the microsatellite marker within the TEL gene on chromosome arm 12p. Two other samples had instability at a microsatellite marker close to CDKN2/p16 on 9p; one of these samples had a homozygous deletion at 9p21. The fifth sample had instability at the microsatellite marker on 6q, which we have found is a frequent region of loss of heterozygosity in childhood ALL.
Taken together, instability was rare in childhood ALL, but was localized to the three most frequently deleted chromosome regions in childhood ALL, suggesting that localized microsatellite instability may identify a fragile chromosomal region which could result in alteration of surrounding target genes and lead to leukaemia.     

一氧化氮等自由基与脑出血关系的研究

目的探讨一氧化氮等自由基与脑出血的关系。方法检测１３３例脑出血患者和１００例健康对照者血浆一氧化氮（Ｐ－ＮＯ）、维生素Ｃ（Ｐ－ＶＣ）、维生素Ｅ（Ｐ－ＶＥ）、β－胡萝卜素（Ｐ－β－ＣＡＲ）和过氧化脂质（Ｐ－ＬＰＯ）含量及红细胞超氧化物歧化酶（Ｅ－ＳＯＤ）、过氧化氢酶（Ｅ－ＣＡＴ）、谷胱甘肽过氧化物酶（Ｅ－ＧＳＨ－Ｐｘ）活性和过氧化脂质（Ｅ－ＬＰＯ）含量。结果与对照组比较,患者组Ｐ－ＮＯ、Ｐ－ＬＰＯ、Ｅ－ＬＰＯ均值显著升高（Ｐ＜０．００１）,Ｐ－ＶＣ、Ｐ－ＶＥ、Ｐ－β－ＣＡＲ、Ｅ－ＳＯＤ、Ｅ－ＣＡＴ、Ｅ－ＧＳＨ－Ｐｘ均值显著降低（Ｐ＜０．００１）;逐步回归发现,患者病情（ＮＤＳ）与Ｐ－ＮＯ、Ｐ－ＶＣ、Ｅ－ＬＰＯ值相关最为密切,颅内血肿量与Ｐ－ＮＯ、Ｐ－ＶＥ、Ｅ－ＬＰＯ值相关最为密切。结论脑出血患者体内自由基反应病理性加剧,氧化抗氧化平衡严重失     

Hemorheological and hemodynamic effects of high molecular weight polyethylene oxide solutions

Hemorheological and hemodynamic effects of high molecular weight polyethylene oxide (PEO) solutions have been studied in vitro and in vivo at 30 experimental dogs. The rheological behaviour of the PEO solutions and of blood samples has been assessed by rotational viscometers at 20 degrees C, 25 degrees C and 37 degrees C. An addition of PEO solutions to the blood in vitro has modified its rheological behavior, depending on the shear rates, concentration and temperature. Saline with aqueous PEO solutions at the concentration of 500 ppm has been infused into the blood circulation of the experimental dogs to achieve the total concentration in blood of 20-30 ppm. The following parameters cardiac output, mean arterial blood pressure, central venous pressure, pulse frequency, blood volume flow in the femoral artery, total vascular resistance and blood viscosity before and after the infusion of PEO solutions have been studied. The main observed effect was a decrease of the hemodynamic resistance in the cardiovascular system up to 40% below the baseline after infusion of PEO solutions.     

Pro-resolution immunological networks: binding immunoglobulin protein and other resolution-associated molecular patterns

Appropriate regulation and subsequent resolution of acute inflammatory events is critical to the prevention of autoinflammatory diseases. Indeed, the chronic inflammation observed in diseases such as RA is at least partially consequent on the failure of endogenous immunoregulation. Current RA therapies (e.g. anti-TNF-α inhibitors and MTX) inhibit components of the inflammatory disease process without directly promoting the resolution of inflammation. We propose that the next generation of RA therapeutics will complement and augment endogenous immunoregulatory and pro-resolution immunological networks, thus promoting the definitive resolution of inflammation rather than temporary immunological control. Of particular interest with respect to this therapeutic approach is binding immunoglobulin protein [BiP; also known as glucose-regulated protein-78 (GRP78)], a member of the recently defined resolution-associated molecular pattern (RAMP) family of molecules. In this review, we consider the preclinical evidence from experiments in mouse and man that suggests BiP and other members of the RAMP family have the potential to herald a new generation of immunotherapeutics.     

PRV-1 mRNA expression and other molecular markers in polycythemia rubra vera

During the past 4 years, the first molecular markers for polycythemia vera (PV) have been described. These markers include decreased expression of the thrombopoietin receptor c-Mpl, increased expression of the surface receptor polycythemia rubra vera-I, and insulin-like growth factor-I hypersensitivity. Characterization of these abnormalities has allowed the development of the first molecular diagnostic tools for PV. However, despite these advances, the molecular mechanisms leading to the development of PV remain poorly understood. This review summarizes and evaluates recent advances in our understanding of molecular aberrations in PV.     

Prolactin activation of mammary nitric oxide synthase: molecular mechanisms

Prolactin (PRL) is capable of stimulating both calcium and nitric oxide (NO) accumulation in mammary epithelial cells within 15min. A calcium ionophore was also able to stimulate NO levels to an extent similar to that generated by PRL. Furthermore, maximal concentrations of PRL and the ionophore were not additive, suggesting that they were both using the same pathway, i.e. calcium. Finally, the depletion of intracellular calcium completely abrogated the effect of PRL on NO production. No other pathway known to affect NO synthase (NOS) influenced the action of PRL. Specifically, manipulations of protein phosphatase 2B, protein kinase B (PKB), protein kinase C (PKC), and arginine transport did not alter the activation of NOS by PRL. Therefore, the ability of PRL to stimulate NO production at 15min can be completely explained by its ability to elevate intracellular calcium.     

Yin Zhi Huang and other plant-derived preparations: where herbal and molecular medicine meet

A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. Yin Zhi Huang, a decoction of Yin Chin (Artemisia capillaris) and three other herbs, is widely used in Asia to prevent and treat neonatal jaundice. We recently identified the constitutive androstane receptor (CAR, NR1I3) as a key regulator of bilirubin clearance in the liver. Here we show that treatment of WT and humanized CAR transgenic mice with Yin Zhi Huang for 3 days accelerates the clearance of intravenously infused bilirubin. This effect is absent in CAR knockout animals. Expression of bilirubin glucuronyl transferase and other components of the bilirubin metabolism pathway is induced by Yin Zhi Huang treatment of WT mice or mice expressing only human CAR, but not CAR knockout animals. 6,7-Dimethylesculetin, a compound present in Yin Chin, activates CAR in primary hepatocytes from both WT and humanized CAR mice and accelerates bilirubin clearance in vivo. We conclude that CAR mediates the effects of Yin Zhi Huang on bilirubin clearance and that 6,7-dimethylesculetin is an active component of this herbal medicine. CAR is a potential target for the development of new drugs to treat neonatal, genetic, or acquired forms of jaundice. [Abstract reproduced by permission of J Clin Invest 2004;113:137-143].     

A molecular basis for nitric oxide sensing by soluble guanylate cyclase

Nitric oxide (NO) functions as a signaling agent by activation of the soluble isoform of guanylate cyclase (sGC), a heterodimeric hemoprotein. NO binds to the heme of sGC and triggers formation of cGMP from GTP. Here we report direct kinetic measurements of the multistep binding of NO to sGC and correlate these presteady state events with activation of enzyme catalysis. NO binds to sGC to form a six-coordinate, nonactivated, intermediate (k(on) > 1.4 x 10(8) M(-1).s(-1) at 4 degrees C). Subsequent release of the axial histidine heme ligand is shown to be the molecular step responsible for activation of the enzyme. The rate at which this step proceeds also depends on NO concentration (k = 2.4 x 10(5) M(-1).s(-1) at 4 degrees C), thus identifying a novel mode of regulation by NO. NO binding to the isolated heme domain of sGC was also rapid (k = 7.1 +/- 2 x 10(8) M(-1).s(-1) at 4 degrees C); however, no intermediate was observed. The data show that sGC acts as an extremely fast, specific, and highly efficient trap for NO and that cleavage of the iron-histidine bond provides the driving force for activation of sGC. In addition, the kinetic data indicate that transport or stabilization of NO is not necessary for effective signal transmission.