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At least 307 records · Page 17Linked to original sources
PubMed2000

Pathogenesis of colorectal cancer.

The development of colorectal cancer has been viewed as an ordered process in which three main phases can be identified: initiation, promotion and progression. There is definite proof that stable alterations of the structure or sequence of DNA (mutations) represent the initiating event; these are followed by an uncontrolled expansion of the neoplastic clones which characterizes tumoural growth. Several classes of genes have been identified foncogenes, tumour suppressor genes and "mutator" genes) the alterations of which are important in the initiation as well as in the promotion and progression of tumours. Colorectal cancer, therefore, results from a series of genetic changes which lead to the progressive and irreversible loss of normal control of cell growth and differentiation. Available evidence is consistent with the hypothesis that there are several molecular pathways underlying the passage from normal mucosa to colorectal carcinoma, thus explaining the existence of intestinal tumours with a different biological nature, which may represent specific targets for prevention and cure. Well-defined molecular pathways have been identified for: A) sporadic colorectal cancer ("Loss of heterozygosity pathway"); B) familial adenomatous polyposis and related polyposis syndromes; C) hereditary non-polyposis colorectal cancer ("mutator genes/microsatellite instability pathway"); D) cancer developing in inflammatory bowel diseases; E) familial colorectal cancer. Thus, there is consistent and considerable evidence suggesting the existence of several biological pathways leading to the same phenotypical expression (i.e., colorectal cancer), and it is likely that additional pathways will be clarified in the future. From a practical point of view, tumours with a diverse biology might offer different and more effective preventive and curative approaches.

Colorectal Neoplasms↗
PubMed2006

The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors?

Neuroendocrine (NE) tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma are metastatic in nature, and secrete biogenic amines and hormones. In this review, we will discuss the possibility that activation of the Ras/Raf signaling pathway may be a therapeutic target for patients with select NE tumors. In-vitro activation of Raf-1 in NE tumors either by expression of the ectopic catalytic domain of Raf-1 or by a pharmacologic drug, ZM336372, resulted in growth inhibition. In addition, activation of the Ras/Raf pathway led to a significant reduction in NE markers such as serotonin, chromogranin A and calcitonin. These data support development of Raf-1-activating compounds for treatment of patients with NE tumors of selective subtypes.

Antineoplastic Agents↗
PubMed2005

Molecular pathophysiology of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra. Although the etiology of PD is incompletely understood, the recent discovery of genes associated with rare monogenic forms of the disease, together with earlier studies and new experimental animal models, has provided important and novel insight into the molecular pathways involved in disease pathogenesis. Increasing evidence indicates that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction may represent the principal molecular pathways or events that commonly underlie the pathogenesis of sporadic and familial forms of PD .

Animals↗
PubMed2004

Hypoxia-activated tumor pathways of angiogenesis and pH regulation independent of anemia in head-and-neck cancer.

PURPOSE: Anemia is considered a major factor that counteracts the efficacy of radiotherapy, presumably because of reduced oxygen availability that leads to tumor hypoxia. Nevertheless, anemia is not the only factor defining oxygen availability, because a poor and/or immature vascular network may prevent blood flow and tumor oxygenation. Furthermore, the ability of tumors to upregulate hypoxia-regulated molecular pathways may affect radiosensitivity by mechanisms independent of the traditional concept of "oxygen effect." METHODS AND MATERIALS: In this study, we investigated whether the preoperative blood hemoglobin levels affect the activation status of hypoxia/angiogenic pathways (hypoxia inducible factors [HIF1 alpha and HIF2 alpha], carbonic anhydrase 9, differentiated embryo-chondrocyte protein, vascular endothelial growth factor, and microvessel density), in squamous cell head-and-neck cancer. RESULTS: Hypoxia/angiogenesis pathways were equally activated in tumors, independent of the patient's hemoglobin levels. The expression of HIF alphas was associated with microvessel density (p = 0.01). CONCLUSION: In the present study, we failed to show that a patient's anemia is a main contributor to the activation of hypoxia-regulated molecular pathways in squamous cell head-and-neck cancer. Impaired intratumoral blood flow or tumor-related gene/protein pathologic features may account for this finding. Targeting the hypoxia-regulated molecular cascade emerged as a complementary radiosensitization strategy for a large group of patients with hypoxic tumors, who are unlikely to benefit from conventional approaches aiming to improve intratumoral oxygen delivery through anemia correction.

Anemia↗
PubMed2002

Roger S. Mitchell lecture. Uses of expression microarrays in studies of pulmonary fibrosis, asthma, acute lung injury, and emphysema.

Expression microarrays are a powerful tool that could provide new information about the molecular pathways regulating common lung diseases. To exemplify how this tool can be useful, selected examples of informative experiments are reviewed. In studies relevant to asthma, the cytokine interleukin-13 has been shown to produce many of the phenotypic features of this disease, but the cellular targets in the airways and the molecular pathways activated are largely unknown. We have used microarrays to begin to dissect the different transcriptional responses of primary lung cells to this cytokine. In experiments designed to identify global transcriptional programs responsible for regulating lung inflammation and pulmonary fibrosis, we performed microarray experiments on lung tissue from wild-type mice and mice lacking a member of the integrin family know to be involved in activation of latent transforming growth factor (TGF)-beta. In addition to identifying distinct cluster of genes involved in each of these processes, these studies led to the identification of novel pathways by which TGF-beta can regulate acute lung injury and emphysema. Together, these examples demonstrate how careful application and thorough analysis of expression microarrays can facilitate the discovery of novel molecular targets for intervening in common lung diseases.

Animals↗
PubMed2004

Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy.

The maintenance of adult skeletal muscle mass is ensured by physical exercise. Accordingly, physiological and pathological situations characterized by either impaired motor neuron activity, reduced gravity (microgravity during space flights), or reduced physical activity result in loss of muscle mass. Furthermore, a plethora of clinical conditions, including cancer, sepsis, diabetes, and AIDS, are associated with varying degrees of muscle atrophy. The cellular and molecular pathways responsible for maintaining the skeletal muscle mass are not well defined. Nonetheless, studies aimed at the understanding of the mechanisms underlying either muscular atrophy or hypertrophy have begun to identify the physiological determinants and clarify the molecular pathways responsible for the maintenance of muscle mass.

Animals↗
PubMed2005

Molecular mechanisms of trophoblast survival: from implantation to birth.

Fetal development depends upon a coordinated series of events in both the embryo and in the supporting placenta. The initial event in placentation is appropriate lineage allocation of stem cells followed by the formation of a spheroidal trophoblastic shell surrounding the embryo, facilitating implantation into the uterine stroma and exclusion of oxygenated maternal blood. In mammals, cellular proliferation, differentiation, and death accompany early placental development. Programmed cell death is a critical driving force behind organ sculpturing and eliminating abnormal, misplaced, nonfunctional, or harmful cells in the embryo proper, although very little is known about its physiological function during placental development. This review summarizes current knowledge of the cell death patterns and molecular pathways governing the survival of cells within the blastocyst, with a focus on the trophoblast lineage prior to and after implantation. Particular emphasis is given to human placental development in the context of normal and pathological conditions. As molecular pathways in humans are poorly elucidated, we have also included an overview of pertinent genetic animal models displaying defects in trophoblast survival.

Animals↗
PubMed2001

Multipotent hematopoietic cell lines derived from C/EBPalpha(-/-) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation.

The transcription factor C/EBPalpha is an important mediator of granulocyte differentiation and regulates the expression of multiple granulocyte-specific genes including the granulocyte-colony-stimulating factor (G-CSF) receptor, neutrophil elastase, and myeloperoxidase. Indeed C/EBPalpha knockout mice display a profound block in granulocyte differentiation. To study this block in granulocytic differentiation in more detail, retroviral vector-mediated transduction of a dominant-negative retinoic acid receptor was used to establish hematopoietic growth factor-dependent, lympho-myeloid progenitor cell lines from the fetal livers of both the C/EBPalpha knockout animals (C/EBPalpha(-/-)) and their heterozygous littermates (C/EBPalpha(+/-)). Surprisingly, the C/EBPalpha(-/-) cell lines displayed significant spontaneous granulocytic differentiation, and this differentiation was markedly enhanced when the cells were stimulated with granulocyte macrophage (GM)-CSF. This GM-CSF-mediated differentiation was associated with the up-regulation of G-CSF receptor mRNA, and the combination of GM-CSF and G-CSF generated more than 95% mature neutrophils in the C/EBPalpha(-/-) cultures. The addition of all-trans retinoic acid also enhanced this granulocytic differentiation of the cultured C/EBPalpha(-/-) cells, indicating that the activated retinoic acid receptors can enhance granulocytic differentiation through a molecular pathway that is independent of C/EBPalpha. These studies clearly indicate that terminal granulocytic differentiation associated with the up-regulation of C/EBPalpha-responsive genes can occur in the absence of C/EBPalpha, and they indicate the existence of multiple independent molecular pathways potentially used by primitive hematopoietic precursors that can lead to the development of mature granulocytes.

Animals↗
PubMed2002

Regulation of nuclear factor-kappaB by corticotropin-releasing hormone in mouse thymocytes.

CRH, a major mediator of the stress response, has been shown to exert potent immunomodulatory effects in vivo, through mechanisms that have not been elucidated yet. To determine the molecular pathways mediating the proinflammatory effects of peripheral CRH, we studied its role in the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor crucial for the regulation of a variety of inflammatory mediator genes. Our studies demonstrate that, in mouse thymocytes, CRH induces the NF-kappaB DNA-binding activity in a time- and dose-dependent manner, with parallel degradation of its inhibitor protein inhibitor of NF-kappaB. The effect of CRH is not inhibited by dexamethasone and is mediated by the protein kinase A and protein kinase C signaling pathways. In vivo, we show that CRH-deficient mice respond to lipopolysaccharide administration by reduced activation of thymus NF-kappaB, despite their significantly elevated proinflammatory cytokine and their low corticosterone levels. These findings suggest a putative molecular pathway mediating the proinflammatory effects of peripheral CRH through induction of the NF-kappaB DNA binding activity.

Animals↗
PubMed2005

Free radicals as triggers of brain edema formation after stroke.

Brain edema is a leading cause of death after stroke. Cytotoxic edema, which is most severe in astrocytes, begins within a few minutes of adenosine triphosphate depletion and reflects the ultimate infarct size. Vasogenic edema is caused by uncontrolled fluid leakage from the blood to the brain parenchyma through a weakened blood-brain barrier (BBB) and contributes to an actual net volume increase of the brain, which often leads to death. Recent research on ischemia-induced injury mechanisms of the microvasculature has led to the disclosure of the mechanisms and cellular pathways leading to BBB breakdown. In addition, the introduction of magnetic resonance imaging to clinical practice has enabled the evaluation of edema severity in stroke patients and differentiation between cytotoxic and vasogenic edema. Free radicals exert their deleterious actions during both cytotoxic and vasogenic edema. They can contribute to BBB disruption directly and can also trigger molecular pathways related to the dysfunction of ion transporters in the cell membrane and those related to increased vascular permeability. The development of effective therapeutic strategies aimed at reducing brain edema based on targeting specific molecular pathways involved may reduce death and disability from stroke.

Blood-Brain Barrier↗
PubMed2003

Genetics of sleep and sleep disorders.

Sleep has been observed in all vertebrates studied and in several invertebrates, notably the fruit fly Drosophila melanogaster. In all species, a substantial portion of life is spent in this behavioral state and disturbed sleep or lack of sleep has immediate negative impacts on performance and health. Although it is agreed upon that sleep fulfills a fundamental biological need, the function of sleep remains an enigma. Because the expression and regulation of sleep and some sleep disorders have strong genetic components, the recent progress in human, mouse, and fruit-fly genome sequencing projects have given rise to the expectation that the molecular pathways underlying sleep disorders and sleep regulation or even function can now be more readily identified. We review here available genetic data both from basic sleep research and sleep disorders with emphasis on recent advances in our understanding of the molecular basis of the homeostatic regulation of sleep. Recent studies in the dog, the mouse, and the fruit-fly have begun to reveal exciting new molecular pathways that regulate sleep. This illustrates that only the continued use of multiple animal models and genetic approaches will ensure a rapid progress in the relatively new field of sleep genetics.

Animals↗
PubMed2001

An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration.

Age-related macular degeneration (AMD) is a blinding disease that afflicts millions of adults in the Western world. Although it has been proposed that a threshold event occurs during normal aging which leads to AMD, the sequelae of biochemical, cellular, and/or molecular events leading to the development of AMD are poorly understood. Although available data provide strong evidence that a significant proportion of AMD has a genetic basis, no gene(s) has yet been identified that causes a significant proportion of AMD. Moreover, no major molecular pathways involved in the etiology of this disease have been elucidated.Drusen, pathological deposits that form between the retinal pigmented epithelium (RPE) and Bruch's membrane, are significant risk factors for the development of AMD. In our view, the development of testable new hypotheses of drusen origins has been hindered significantly by the absence of a comprehensive profile of their molecular composition. In this review, we describe an integrated ultrastructural, histochemical, molecular biological, and biochemical approach to identify specific molecular pathways associated with drusen biogenesis. The implicit assumption underlying these recent investigations has been that a thorough understanding of the composition of drusen and source(s) of drusen-associated material is likely to provide fresh insight into the pathobiology underlying AMD. Significantly, these studies have revealed that proteins associated with inflammation and immune-mediated processes are prevalent among drusen-associated constituents. Transcripts that encode a number of these molecules have been detected in retinal, RPE, and choroidal cells. These data have also lead to the observations that dendritic cells, potent antigen-presenting cells, are intimately associated with drusen development and that complement activation is a key pathway that is active both within drusen and along the RPE-choroid interface. We propose herein a unifying hypothesis of drusen biogenesis that attempts to incorporate a large body of new and previously published structural, histochemical, and molecular data pertaining to drusen composition and development. This theory is put forth with the acknowledgment that numerous AMD genotypes may exist. Thus, only some aspects of the proposed hypothesis may be involved in any given AMD genotype. Importantly, this hypothesis invokes, for the first time, the potential for a direct role of cell- and immune-mediated processes in drusen biogenesis. We acknowledge that the proposed hypothesis clearly represents a paradigm shift in our conceptualization pertaining to pathways that participate in the development of drusen and age-related macular degeneration. It is our hope that other investigators will test, validate and/or refute various aspects of this hypothesis, and in so doing, increase our overall understanding of the biological pathways associated with early AMD.

Aging↗
PubMed1999

Renal bradykinin receptors: localisation, transduction pathways and molecular basis for a possible pathological role (review).

Kinins are biologically active peptides that exert their effects by activating two seven transmembrane G-protein coupled receptors termed B1 and B2 which have only about 36% of homology. The major kinin peptide under physiological conditions, bradykinin (BK), modulates renal haemodynamics and function. Under physiological conditions most BK effects involve bradykinin B2-receptors. Studies on the intra-cellular transduction pathways, the regulation of the expression and the localisation of these receptors along the nephron, as well as the first studies on transgenic mice models, have allowed to better define the role of these receptors under physiological and pathological conditions. The role of the renal B1-receptor, induced in a variety of pathologies related to inflammation, is poorly understood. Recent investigations on the molecular mechanism of B1-receptor induction and its detailed renal localisation have shown that under inflammatory conditions this kinin receptor might be of importance. B2-receptors are suggested to be involved in part of the renoprotective effects of angiotensin converting enzyme (ACE)-inhibitors in insulin-dependent diabetes. However, ACE-inhibitor treatment, resulting also in an increased B1-agonist concentration might result in homologous induction and activation of the B1-receptor.

Humans↗
PubMed2005

Molecular mechanisms in Schwann cell survival and death during peripheral nerve development, injury and disease.

The mechanisms determining the fate of Schwann cells during disease and injury of the adult mammalian peripheral nervous system (PNS) are becoming defined by current advances in molecular neurobiology. It is now apparent that the molecular pathways which regulate the production of the mature myelinating Schwann cell during development may also apply to degenerative and regenerative mechanisms following PNS disease. This review outlines neurobiological responses of Schwann cells during development, injury and disease in order to define the molecular pathways which regulate these crucial events. These mechanisms have implications for our attempts to intervene pharmacologically during pathologies of the PNS.

Animals↗
PubMed2001

Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis.

In the last 10 years, evidence has accumulated that overexpression of Met protein is a distinguishing feature of almost every case of well-differentiated papillary carcinoma. Increased expression of the protein is probably due to enhanced transcription of the MET gene and/or to post-transcriptional mechanisms. So far, alterations of the MET gene have not been recognized, but evidence has been provided that activated RAS and RET can cause accumulation of MET RNA. Thus, the possibility exists that dysregulation of MET is the final result of different molecular pathways capable of inducing thyroid cell transformation; RET rearrangements might account for some of the cases, but the demonstration that the majority of papillary carcinomas do not have recognized alterations of the RET gene strongly suggests that MET gene dysregulation can also be achieved through other molecular pathways. Dysregulation of MET causes marked accumulation of Met protein in tumour cells that is promptly detected by immunohistochemistry. Thus, overexpression of Met protein might represent an immunohistochemical marker of papillary carcinoma, potentially helpful in problematic cases, but caution is required; moderate expression of Met protein is observed in non-neoplastic thyroid diseases, such as Graves' and Hashimoto's thyroiditis, and reagents active on paraffin sections may have a low affinity and/or low specificity for Met protein, leading to artifactual staining. Met protein-positive papillary carcinoma cells may produce hepatocyte growth factor (HGF) and may activate HGF through the urokinase-type plasminogen activator (uPA) bound to urokinase-type plasminogen activator receptor (uPA-R). Thus, papillary carcinoma cells possess the molecular machinery necessary for a productive HGF/Met interaction. In vitro studies have demonstrated that HGF enhances the motility and invasiveness of tumour cells and induces the synthesis and release of chemokines active in the recruitment of dendritic cells. These observations provide a rational basis for the understanding of two distinguishing features of papillary carcinoma. First, the tumour is often characterized by early metastatic spread to regional lymph nodes and by multifocal involvement of the gland, which suggests highly invasive behaviour. Second, a prominent peritumoural inflammatory reaction is often observed, which suggests cross-talk between tumour cells and the immune system.

Biomarkers, Tumor↗
PubMed1994

Mutagenesis of ras proto-oncogenes in rat liver tumors induced by vinyl chloride.

Vinyl chloride is a DNA-damaging carcinogen which induces liver angiosarcomas in humans and animals. Activation of the Ki-ras 2 gene by a GC-->AT transition at the second base of codon 13 in human liver angiosarcomas associated with occupational exposure to vinyl chloride has been reported recently. In order to compare the molecular pathways of carcinogenesis in humans and animals, Sprague-Dawley rats were exposed to vinyl chloride and hepatic tumors, including two hepatocellular carcinomas and five liver angiosarcomas, were investigated for mutations at codons 12, 13 and 61 of the Ha-ras, Ki-ras and N-ras genes. High molecular weight DNA was amplified by the polymerase chain reaction and point mutations were analyzed by allele specific oligonucleotide hybridization, direct sequencing of polymerase chain reaction products and sequencing after cloning. None of the tumors exhibited a mutation in codons 12, 13 and 61 of the Ki-ras gene, nor in codons 12 of the Ha-ras gene or 61 of the N-ras gene. However, an activating AT-->TA transversion at base 2 of codon 61 of the Ha-ras gene was detected in the two hepatocellular carcinomas. Mutations involving codon 13 (GGC-->GAC) and codon 36 (ATA-->CTA) of the N-ras A gene were detected in two liver angiosarcomas, suggesting that the nature of the ras gene affected by a given carcinogen depends on host factors specific to cell types. Several additional base pair substitutions were found in exon 1 of the N-ras B and C sequences. NIH 3T3 transfection assays and Southern blot analysis of DNA from transformed NIH 3T3 cells confirmed the presence of a dominant activated N-ras gene. These results emphasize the differences in the molecular pathways leading to tumors in humans and rats and within a given species between different cell types.

3T3 Cells↗
PubMedDate not supplied

The molecular basis of hypertension.

Hypertension is a substantial public health problem affecting about 25% of the population in industrialized societies. The disorder is responsible for many common causes of morbidity and mortality. Despite the important role of hypertension as a cause of disease, its pathogenesis remains largely unknown. The application of genetic approaches to rare monogenic (Mendelian) forms of hypertension and hypotension has begun to delineate molecular pathways underlying human blood pressure variation, defining disease pathogenesis and identifying targets for therapeutic intervention. In all cases the pathophysiology is altered net renal salt reabsorption. Mutations are either affecting circulating mineralocorticoid hormones or renal ion channels and transporters. Examples are glucocorticoid-remediable aldosteronism (GRA), Liddle's syndrome, the syndrome of hypertension exacerbated in pregnancy, and apparent mineralocorticoid-excess (AME). Recently, alterations in genes of a novel serine-threonine kinase family (WNK1 and WNK4) were identified causing pseudohypoaldosteronism type II. The molecular pathway of this syndrome remains unclear. Additionally, there is the syndrome of hypertension associated with brachydactyly type E (Bilginturan's syndrome), for which the molecular mechanism has yet to be identified.

Aldosterone↗
PubMed2004

Modulation of apoptotic signalling by carotenoids in cancer cells.

There is a growing body of literature on the role of beta-carotene and other carotenoids in human chronic diseases, including cancer. While epidemiological evidence shows that a high dietary intake of fruits and vegetables rich in carotenoids is associated with a reduced risk for cancer, results from intervention trials indicate that supplemental beta-carotene enhances the risk of developing lung cancer incidence and mortality among smokers. A possible mechanism which can explain the dual role of carotenoids as both beneficial and harmful agents in cancer is that their excess or deficiency may bring about changes in molecular pathways involved in apoptotic signalling. Carotenoid ability in inhibiting or in enhancing apoptosis depends on several factors: carotenoid concentration, concerted action of multiple micronutrients, cell type, and redox status. This review summarizes the available evidence for a modulatory action of carotenoids on apoptosis and focuses on the main molecular pathways involved in this process.

Apoptosis↗