Inhibition of angiogenesis by NSAIDs: molecular mechanisms and clinical implications

Angiogenesis, the formation of new capillary blood vessels, is a fundamental process essential for reproduction and embryonic development. It is crucial to the healing of tissue injury because it provides essential oxygen and nutrients to the healing site. Angiogenesis is also required for cancer growth and progression since tumor growth requires an increased nutrient and oxygen supply. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs worldwide for treating pain, arthritis, cardiovascular diseases, and more recently for colon cancer prevention. However, NSAIDs produce gastrointestinal ulcers and delay ulcer healing. Recently NSAIDs have been demonstrated to inhibit angiogenesis, but the underlying mechanisms are only beginning to be elucidated. The inhibition of angiogenesis by NSAIDs is a causal factor in the delay of ulcer healing, and it is becoming clear that this is also likely to be one of the mechanisms by which NSAIDs can reduce or prevent cancer growth. Based on the experimental data and the literature, the mechanisms by which NSAIDs inhibit angiogenesis appear to be multifactorial and likely include local changes in angiogenic growth factor expression, alteration in key regulators and mediators of vascular endothelial growth factor (VEGF), increased endothelial cell apoptosis, inhibition of endothelial cell migration, recruitment of inflammatory cells and platelets, and/or thromboxane A2 mediated effects. Some of these mechanisms include: inhibition of mitogen-activated protein (Erk2) kinase activity; suppression of cell cycle proteins; inhibition of early growth response (Egr-1) gene activation; interference with hypoxia inducible factor 1 and VEGF gene activation; increased production of the angiogenesis inhibitor, endostatin; inhibition of endothelial cell proliferation, migration, and spreading; and induction of endothelial apoptosis.     

脑缺血损伤的分子机制研究进展

脑缺血疾病具有发病率高、死亡率高的特点 ,严重危害人类健康。尽管近几十年来对脑缺血进行了大量的研究[2 8- 3 0 ] ,但急性脑缺血的预后仍相当差。究其原因是由于脑缺血损伤的机制十分复杂 ,缺乏有效的干预手段。它的复杂性主要表现在 :脑缺血类型的复杂性 (包括局灶的或全脑的 ,完全的或不完全的 ,短暂的或永久的 )和脑缺血损伤分子机制在时空变化上的复杂性以及各作用因子间相互影响的复杂性。因此 ,迄今为止没有一种机制能完全阐明脑缺血的损伤机制。现认为参与脑缺血损伤的分子机制有兴奋性氨基酸的释放、钙离子稳态失衡、自由基的形…     

Possible molecular mechanisms of brain dysfunction in phenylketonuria]

Recent experimental data are summarized about changes in the functioning of calcium ion channels in clonal cellular lines (pheochromocytoma PC12) and hippocampal neurons of newborn rats on the background of altered intracellular level of aromatic amino acid L-tyrosine or its precursors L-phenylalanine. Elevation of the level of L-phenylalanine persistently down-regulated the high-threshold voltage-operated calcium channels in both types of cells without affecting the low-threshold ones in hippocampal neurons. This depression could be to some extent reversed by elevation of the level of L-tyrosine. Thus both amino acids seem to exert a long-lasting antagonistic modulatory effect on the corresponding channels, mediated probably through changes in tyrosylation of some cytoskeletal proteins. The participation of these molecular mechanisms in brain dysfunction during congenital disease phenylketonuria is suggested.     

Cellular and molecular mechanisms of epilepsy in the human brain

Animal models have provided invaluable data for identifying the pathogenesis of epileptic disorders. Clearly, the relevance of these experimental findings would be strengthened by the demonstration that similar fundamental mechanisms are at work in the human epileptic brain. Epilepsy surgery has indeed opened the possibility to directly study the functional properties of human brain tissue in vitro, and to analyze the mechanisms underlying seizures and epileptogenesis. Here, we summarize the findings obtained over the last 40 years from electrophysiological, histochemical and molecular experiments made with the human brain tissue. In particular, this review will focus on (i) the synaptic and non-synaptic properties of neocortical neurons along with their ability to produce synchronous activity; (ii) the anatomical and functional alterations that characterize limbic structures in patients presenting with mesial temporal lobe epilepsy; (iii) the issue of antiepileptic drug action and resistance; and (iv) the pathophysiology of seizure genesis in Taylor's type focal cortical dysplasia. Finally, we will address some of the problems that are inherent to this type of experimental approach, in particular the lack of proper controls and possible strategies to obviate this limitation.     

Proteomic analysis of mechanisms of hypoxia-induced apoptosis in trophoblastic cells

Preeclampsia is often accompanied by hypoxia of the placenta and this condition induces apoptosis in trophoblastic cells. The aim of this study was to characterize global changes of apoptosis-related proteins induced by hypoxia in trophoblastic cells so as to clarify the mechanism of hypoxia-induced apoptosis by using the PoweBlot, an antibody-based Western array. Human choriocarcinoma cell line JAR was cultured for 24 hours under aerobic and hypoxic conditions. Hypoxia induced apoptosis accompanied by increased expression of Bcl-x, Caspase-3 and -9, Hsp70, PTEN, and Bag-1. Bad, pan-JNK/SAPK-1, Bcl-2, Bid, and Caspase-8 showed decreased expression. Hypoxia-induced apoptosis was increased with the transfection of a bag-1 antisense oligonucleotide. The bag-1 antisense oligonucleotide affected the expression of Bid, Bad, Bcl-2, JNK, and phosphorylated JNK, although expression of PTEN and Bcl-X did not change. Bag-1 may inhibit apoptosis by suppressing the expression of Bid and Bad. It may also enhance apoptosis by inhibiting the expression of Bcl-2 and by modulating phosphorylation of JNK. Both mitochondrial and stress-activated apoptosis pathways played important roles in the hypoxia induced cell death of trophoblastic cells. These findings will contribute to establish new approach to detect hypoxic stress of the placenta, which leads to preeclampsia and other hypoxia-related obstetrics complications.     

New insights into genetic and molecular mechanisms of brain degeneration in tauopathies

Abundant neurofibrillary lesions consisting of the microtubule associated protein tau and amyloid β peptide deposits are the defining lesions of Alzheimer's disease. Prominent filamentous tau pathology and brain degeneration in the absence of extracellular amyloid deposition characterize a number of other neurodegenerative disorders (i.e. progressive supranuclear palsy, corticobasal degeneration, Pick's disease) collectively referred to as tauopathies. The discovery of multiple tau gene mutations that are pathogenic for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 in many kindreds, as well as the demonstration that tau polymorphisms are genetic risk factors for sporadic tauopathies, directly implicate tau abnormalities in the onset/progression of neurodegenerative disease. Different tau gene mutations may be pathogenic by impairing the functions of tau or by perturbing the splicing of the tau gene, thereby resulting in biochemically and structurally distinct tau aggregates. However, since specific polymorphisms and mutations in the tau gene lead to diverse phenotypes, it is plausible that additional genetic or epigenetic factors influence the clinical and pathological manifestations of both familial and sporadic tauopathies. Thus, efforts to develop animal models of tau-mediated neurodegeneration should provide further insights into the onset and progression of tauopathies as well as Alzheimer's disease, and they could accelerate research to discover more effective therapies for these disorders.     

Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies.     

Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Background  

We previously reported an HLA-A24-restricted cytotoxic T-cell epitope, Survivin-2B80-88, derived from a splice variant of survivin, survivin-2B. In this report, we show a novel HLA-A24-restricted T-cell epitope, Survivin-C58, derived from a wild type survivin, and compared their immunogenicity in oral cancer patients.     

VEGF通过上调CCN2促HUVEC迁移和血管生成

目的 探讨血管内皮生长因子(VEGF)诱导的成骨细胞中结缔组织生长因子(CTGF/CCN2)对人脐静脉血管内皮细胞(HUVECs)的影响.方法 用Real time PCR法及ELISA法检测VEGF诱导成骨细胞(OSE)中CCN2含量;制备成骨细胞(OSE)上清液;将细胞分为control组、OSE组和VEGF-OSE组(n=3).用小干扰RNA (siRNA)转染法抑制成骨细胞中CCN2的表达;Transwell法检测内皮细胞迁移;Matrigel实验检测管样结构形成能力.结果 VEGF呈时间和剂量依赖性上调成骨细胞中CCN2 mRNA和蛋白的表达;CCN2可促进内皮细胞的迁移和管样结构形成(P＜0.05),当CCN2被siRNA基因沉默或者加入CCN2抗体后,CCN2对内皮细胞迁移和管样结构形成的促进作用均受到明显抑制(P＜0.05).结论 VEGF通过上调成骨细胞中CCN2的表达,促内皮细胞(HUVECs)的迁移和血管生成.     

The molecular control of angiogenesis

Angiogenesis is a key event in a broad range of pathological conditions including both diseases with an enhanced and insufficient angiogenesis. Angiogenesis is often initiated with vasodilation accompanied by an increase in vascular permeability. After destabilization of the vessel wall and degradation of the surrounding extracellular matrix, extravasation of plasma proteins provides a provisional scaffold for the migration of endothelial cells. Endothelial cell proliferation and migration themselves are under tight control by a balance of angiogenesis inducers and inhibitors. A large number of angiogenic factors work together in a highly coordinated manner to induce endothelial cell outgrowth and the formation of functional vessels. On the other hand, angiostatic factors may play a critical role in the pathogenesis of ischemic diseases and contribute to the termination of physiological angiogenesis. Angiogenesis ends with the recruitment of pericytes and smooth muscle cells, which stabilize the newly formed vessel. The rapid increase in the knowledge about the molecular mechanisms of angiogenesis has led to first treatment trials in diseases with both enhanced and reduced angiogenesis. Although initial results are promising, much more work has to be done to consider anti-angiogenic or pro-angiogenic approaches as reliable therapeutic tools.     

Pathogenic mechanisms in ischemic damage: a computational study

The pathogenesis of penumbral tissue infarction during acute ischemic stroke is controversial. This peri-infarct tissue may subsequently die, or survive and recuperate, and its preservation has been a prime goal of recent therapeutic trials in acute stroke. Two major hypotheses currently under consideration are that penumbral tissue is recruited into an infarct by cortical spreading depression (CSD) waves, or by a non-wave self-propagating process such as glutamate excitotoxicity (GE). Careful experimental attempts to discriminate between these two hypotheses have so far been quite ambiguous. Using a computational metabolic model of acute focal stroke we show here that the spatial patterns of tissue damage arising from artificially induced foci of infarction having specific geometric shapes are inherently different. This is due to the distinct propagation characteristics underlying self-regenerating waves and non-wave diffusional processes. The experimental testing of these predicted spatial patterns of damage may help determine the relative contributions of the two pathological mechanisms hypothesized for ischemic tissue damage.     

Apoptosis in the ovary: molecular mechanisms

Cell death was first described in rabbit ovaries (Graaffian follicles), the phenomenon being called 'chromatolysis' rather than apoptosis. In humans, the ovarian endowment of primordial follicles is established during fetal life. Apoptotic cell death depletes this endowment by at least two-thirds before birth, executed with the help of several players and pathways conserved from worms to humans. To date, apoptosis has been reported to be involved in oogenesis, folliculogenesis, oocyte loss/selection and atresia. Several pro-survival and pro-apoptotic molecules are involved in ovarian apoptosis with the delicate balance between them being the determinant for the final destiny of the follicular cells. This review critically analyses the current knowledge about the biological roles of these molecules and their relevance to the dynamics of follicle development. It also presents the existing literature and assesses the gaps in our knowledge.     

On the mechanisms of the hypoxia-induced increase of 2,3-diphosphoglycerate in erythrocytes

Summary Hypoxia induces in rats a rather rapid increase of the concentration of 2,3-DPG in red blood cells. This increase is reversed when the animals are returned to normal conditions. Pigeons do not respond to hypoxia with an increase of inositol hexaphosphate concentration in their erythrocytes.In rats exposed for 24 h to gas mixtures containing low oxygen and in addition 5% CO₂ the hypoxia induced rise of 2,3-DPG concentration is abolished. The hemoglobin concentration in whole blood is negatively correlated to red cell 2,3-DPG levels in normal as well as in anemic or polycythemic rats.The rate of 2,3-DPG decomposition in human erythrocytes incubated without glucose is the same in the presence and in the absence of oxygen. The incorporation of³²P into 2,3-DPG proceeds faster in deoxygenated than in oxygenated human red blood cells and exceeds considerably the concomitant acceleration of the glycolytic flux rate. These findings indicate that the rate of 2,3-DPG synthesis becomes enhanced in deoxygenated cells. This is mainly due to an elevation of the intracellular pH; the relief of product inhibition of DPG mutase brought about by a greater binding of 2,3-DPG to deoxyhemoglobin seems to be of minor importance.The regulation of 2,3-DPG concentration by the intraerythrocytic pH as well as by the oxygenation state of hemoglobin and the significance of these regulatory mechanisms in inducing and limiting the changes of red cell 2,3-DPG during hypoxia and anemia are discussed.Preliminary reports of parts of this work were presented at the 36th Meeting of the German Physiological Society, Mainz, September 1969 [11] and at the First International Conference on Red Cell Metabolism and Function, Ann Arbor, October 1969 [23].     

Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms

Dietary restriction (reduced calorie intake with nutritional maintenance) can extend lifespan and may increase the resistance of the nervous system to age-related diseases including neurodegenerative disorders. An environment enriched in intellectual and physical activities can also allay many of the adverse effects of aging on the brain. The mechanisms underlying the beneficial effects of dietary restriction and environmental enrichment on the brain involve stimulation of the expression of neurotrophic factors and 'stress proteins'. The neurotrophic factors and stress proteins induced by dietary restriction may protect neurons by suppressing oxyradical production, stabilizing cellular calcium homeostasis and inhibiting a form of programmed cell death called apoptosis. Interestingly, dietary restriction and environmental enrichment also increase numbers of newly-generated neural cells in the adult brain suggesting that these behavioral modifications can increase the brain's capacity for plasticity and self-repair. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is leading to novel therapeutic agents that mimick their beneficial effects.     

Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis.

Cancer-induced angiogenesis is the result of increased expression of angiogenic factors, or decreased expression of anti-angiogenic factors, or a combination of both events. For instance, in colon cancer, the malignant cells, the stromal fibroblasts, and the endothelial cells all exhibit strong staining for cyclooxygenase-2 (COX-2), the rate-controlling enzyme in prostaglandin (PG) synthesis. In various cancer tissues, vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) co-localize with COX-2. Strong COX-2 and VEGF expression is highly correlated with increased tumor microvascular density (MCD); new vessels proliferate in areas of the tumor that express COX-2. Moreover, high MVD is a predictor of poor prognosis in breast and cervical cancers. COX-2 and VEGF expression are elevated in breast and prostate cancer tissues and their cell-lines. In vitro, PGE2 induces VEGE Supernatants of cultured cells from breast, prostate, and squamous cell cancers contain angiogenic proteins such as COX-2 and VEGF that induce in vitro angiogenesis. A selective COX-2 inhibitor, NS-398, restores tumor cell apoptosis, reduces microvascular density, and reduces tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice. The COX-2 produced by a malignant tumor and COX-2 produced by the surrounding host tissue both contribute to new vessel formation, which explains how selective COX-2 inhibition reduces tumor growth where the tumor COX-2 gene has been silenced by methylation.     

AMPK在缺血性脑损伤中的作用

单磷酸腺苷(adenosine monophosphate,AMP)激活的蛋白激酶(AMP-activated protein kinase,AMPK)作为一种能量调控器,在脑缺血时能被激活,活化的AMPK对缺血后脑组织的物质和能量代谢、神经元的损伤和修复、血管和神经的再生等均可产生重要影响.开展AMPK对缺血性脑损伤...