Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury

Recent evidence highlights monoamine oxidases (MAO) as another prominent source of oxidative stress. MAO are a class of enzymes located in the outer mitochondrial membrane, deputed to the oxidative breakdown of key neurotransmitters such as norepinephrine, epinephrine and dopamine, and in the process generate H₂O₂. All these monoamines are endowed with potent modulatory effects on myocardial function. Thus, when the heart is subjected to chronic neuro-hormonal and/or peripheral hemodynamic stress, the abundance of circulating/tissue monoamines can make MAO-derived H₂O₂ production particularly prominent. This is the case of acute cardiac damage due to ischemia/reperfusion injury or, on a more chronic stand, of the transition from compensated hypertrophy to overt ventricular dilation/pump failure. Here, we will first briefly discuss mitochondrial status and contribution to acute and chronic cardiac disorders. We will illustrate possible mechanisms by which MAO activity affects cardiac biology and function, along with a discussion as to their role as a prominent source of reactive oxygen species. Finally, we will speculate on why MAO inhibition might have a therapeutic value for treating cardiac affections of ischemic and non-ischemic origin. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.     

白念珠菌唑类药物耐药相关转录因子研究进展

近年来白念珠菌的感染率呈逐年上升趋势,随着唑类药物的广泛应用,耐药菌株不断增多,已成为临床治疗的一大难题.白念珠菌的耐药机制主要与ERG 11基因的突变和过表达、药物外排泵相关基因表达增多及生物膜的形成等有关,由于转录因子是耐药基因表达的关键调节因子,关于锌簇转录因子与耐药关系的研究越来越多,如TAC 1、MRR 1、MRR 2、UPC 2、NDT 80等,其点突变可引起某些耐药基因的过表达而介导耐药,该领域研究已成为热点,该文就此研究进展做一概述.     

Aberrant silencing of the endocrine peptide gene tachykinin-1 in gastric cancer

Tachykinin-1 (TAC1) is the precursor protein for neuroendocrine peptides, including substance P, and is centrally involved in gastric secretion, motility, mucosal immunity, and cell proliferation. Here we report aberrant silencing of TAC1 in gastric cancer (GC) by promoter hypermethylation. TAC1 methylation and mRNA expression in 47 primary GCs and 41 noncancerous gastric mucosae (NLs) were analyzed by utilizing real-time quantitative PCR-based assays. TAC1 methylation was more prevalent in GCs than in NLs: 21 (45%) of 47 GCs versus 6 (15%) of 41 NLs (p < 0.01). Microsatellite instability was also associated with TAC1 methylation in GCs. There was no significant association between TAC1 methylation and age, gender, stage, histological differentiation, or the presence of Helicobacter pylori. TAC1 mRNA was markedly downregulated in GCs relative to NLs. 5-Aza-2′-deoxycytidine-induced demethylation of the TAC1 promoter resulted in TAC1 mRNA upregulation. Further studies are indicated to elucidate the functional involvement of TAC1 in gastric carcinogenesis.     

药用野生稻TAC克隆转化籼稻的体系初探

采用已构建的药用野生稻TAC文库,比较研究4个籼稻品种在不同培养基的诱导率及愈伤组织对潮霉素抗性。通过2种不同诱导方法产生的愈伤组织,将携带药用野生稻大片段DNA的TAC克隆转化到籼稻品种中的结果表明,除了‘粤香占’以外,其它3个品种在心诱导培养基中添加微量B,后,其愈伤诱导率最高。不同品种的潮霉素筛选适合浓度存在差异,其中‘华粳籼74’的适合筛选浓度为50mg．L-1,‘粤香占’为40mg．L-1。用预培养5d的愈伤组织进行遗传转化,在潮霉素筛选之前先以头孢拉定抑菌处理的,容易获得转基因植株。4个品种中以‘粤香占’的抗性愈伤组织筛选率和分化率最高,分别为22．58％和14．86％。分子检测11株转基因水稻的结果表明,其中8株含有抗性标记基因。据此认为,药用野生稻TAC文库在水稻创新育种中可能有一定的利用前景。     

A novel form of Total Internal Reflection Fluorescence Microscopy (LG-TIRFM) reveals different and independent lipid raft domains in living cells

In the present study we have applied a novel form of Total Internal Reflection Fluorescence Microscopy (LG-TIRFM) in combination with fluorescently labeled cholera toxin to the study of lipid rafts dynamics in living cells. We demonstrate the usefulness of such approach by showing the dynamic formation/disaggregation of islands of cholera toxin on the surface of cells. Using multicolor LG-TIRFM with co-localization studies we show for the first time that two receptors previously identified as constituents of lipid rafts are found on different and independent “raft domains” on the cell plasma membrane. Furthermore, LG-TIRFM studies revealed limited association and dissociation of both domains overtime on different areas of the plasma membrane. The implications of different “raft domains” on cell physiology are discussed.     

Direct and indirect effects of kisspeptin on liver oxidant and antioxidant systems in young male rats

Kisspeptin is a recently discovered hypothalamic peptide which plays an important role in the central control of reproductive functions. We have investigated direct and indirect effects of kisspeptin on the liver oxidative stress in young male rats. Twenty‐four rats were divided into four groups (n = 6/group). First group served as control and received saline. Kisspeptin‐10 was administered to the animals in the second group (20 nmol/rat/day), for a period of 7 days. Rats were given only one dose gosereline (0.9 mg/rat), a GnRH agonist in the third group. The last group received kisspeptin‐10 with gosereline. The activities of catalase, superoxide dismutase (SOD), xanthine oxidase (XO), adenosine deaminase (AD) and level of malondialdehyde were studied in liver tissue. Serum samples were separated for total antioxidant capacity (TAC), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, blood urea nitrogen (BUN), colesterol, high‐density lipoprotein (HDL) and triglyceride. Kisspeptin increased the activities of SOD and catalase (p < 0.05). When compared to the control group, the levels of malondialdehyde, TOS and AST were lower, but levels of BUN, cholesterole, HDL and AD were higher in the other three groups (p < 0.05). In conclusion, our findings suggest that kisspeptin may have antioxidant and thus protective effects on the liver tissue. Copyright © 2010 John Wiley & Sons, Ltd.     

Antarctic bacterial haemoglobin and its role in the protection against nitrogen reactive species

In a cold and oxygen-rich environment such as Antarctica, mechanisms for the defence against reactive oxygen and nitrogen species are needed and represent important components in the evolutionary adaptations. In the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125, the presence of multiple genes encoding 2/2 haemoglobins and a flavohaemoglobin strongly suggests that these proteins fulfil important physiological roles, perhaps associated to the peculiar features of the Antarctic habitat. In this work, the putative role of Ph-2/2HbO, encoded by the PSHAa0030 gene, was investigated by in vivo and in vitro experiments in order to highlight its involvement in NO detoxification mechanisms. The PSHAa0030 gene was cloned and then over-expressed in a flavohaemoglobin-deficient mutant of Escherichia coli, unable to metabolise NO, and the resulting strain was studied analysing its growth properties and oxygen uptake in the presence of NO. We here demonstrate that Ph-2/2HbO protects growth and cellular respiration of the heterologous host from the toxic effect of NO-donors. Unlike in Mycobacterium tuberculosis 2/2 HbN, the deletion of the N-terminal extension of Ph-2/2HbO does not seem to reduce the NO scavenging activity, showing that the N-terminal extension is not a requirement for efficient NO detoxification. Moreover, the ferric form of Ph-2/2HbO was shown to catalyse peroxynitrite isomerisation in vitro, confirming its potential role in the scavenging of reactive nitrogen species. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.     

TAC方案治疗晚期术后乳腺癌疗效观察

目的探讨分析TAC方案治疗晚期术后乳腺癌的临床疗效。方法选取我院自2008年1月至2010年6月收治的76例晚期术后乳腺癌患者,所有患者按随机数法分为实验组与对照组,两组均为38例。实验组接受TAC化疗方案,对照组接受CTF化疗方案,治疗6个疗程后比较两组患者的临床疗效及不良反应发生情况。结果实验组的无进展生存期、总生存期及1—3年生存率均明显优于对照组（P〈0．05）;实验组中性粒细胞减少与恶性呕吐的发生率明显高于对照组（P〈0．05）,两组其余髓内及髓外毒性反应及心脏毒性反应发生率的差异比较均无统计学意义（P〉0．05）。结论TAC方案治疗晚期术后乳腺癌的临床疗效显著,延长了患者术后的生存时间,且不良反应少,值得推广。     

Lipid peroxidation and total antioxidant status in patients with breast cancer

Oxidative stress is considered to be involved in the pathophysiology of all cancers. The aim of this study is to examine oxidative stress and antioxidant status in patients with breast cancer by evaluation of the serum levels of total antioxidant capacity (TAC) and lipid peroxidation products as malondialdehyde (MDA) and lipid hydroperoxide and to investigate the relationship between these parameters, oxidative stress and serum lipids and lipoproteins. In our study, serum TAC, MDA, lipid hydroperoxide, HDL-cholesterol, VLDL-cholesterol, LDL-cholesterol, total cholesterol, triacylglycerol (TAG), albumin and uric acid levels of 56-breast cancer patients in different clinical stages and 18 healthy women were determined. Significantly lower-levels of TAC were detected in patients with breast cancer in comparison to controls (2.01 +/- 0.01 mmol/l and 2.07 +/- 0.03 mmol/l, respectively, p < 0.05). Serum MDA levels of the patients were higher compared to the controls (3.64 +/- 0.25 microM and 2.72 +/- 0.22 microM, respectively, p < 0.05). No significant difference between lipid hydroperoxide levels of patients and controls was found (0.33 +/- 0.05 microM and 0.32 +/- 0.01 microM, respectively, p > 0.05). These data show that lower TAC and higher MDA levels i.e. increased oxidative stress may be related to breast cancer.     

Candesartan antagonizes pressure overload-evoked cardiac remodeling through Smad7 gene-dependent MMP-9 suppression

The present study was designed to investigate the underlying molecular mechanism for Angiotensin II type 1 receptor blockers (ARBs) mediated cardio-protection against pressure overload-induced cardiac remodeling with a focus on Smad7. ROCK-1, Smad3 and fibronectin expressions were increased in male C57BL/6 mice underwent transverse aortic constriction (TAC) for 2weeks. Treatment with Candesartan (2mg/kg per day) could effectively downregulate Smad3 and fibronectin accompanied by upregulating of Smad7. Further data showed that Candesartan inhibited TGF-β1 signal-induced epithelial-to-mesenchymal transition (EMT) through attenuating matrix metalloproteinases (MMP-9), such effect was abolished by knocking-down Smad7. Moreover, TAC for 2weeks caused increased collagen deposition, thickness of left ventricular anterior and posterior wall at end-diastole (LVAWD and LVPWD) and LVEF% reduction, which were reversed by treatment with Candesartan, but failed after knocking-down Smad7. In addition, LV dP/dt(max) and dP/dt(min) were increased by TAC for 2weeks, and treatment with Candesartan or Nifedipine effectively depressed the high levels of dP/dt(min) induced by TAC. However, only Candesartan-mediated protective role in improving cardiac function was suppressed by tail-vein injection of Smad7 siRNA. This study uncovered a novel role for ARBs in preventing pressure overload-induced cardiac remodeling via Smad7 upregulation, which suppressed MMP-9 expression and TGF-β1 signal-mediated EMT progress.