[The ECG 100 years later: electrical contribution to molecular signal pathways].
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Cardiology↗
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Boolean network analysis of a neurotransmitter signaling pathway.
BACKGROUND: A Boolean network is a simple computational model that may provide insight into the overall behavior of genetic networks and is represented by variables with two possible states (on/off), of the individual nodes/genes of the network. In this study, a Boolean network model has been used to simulate a molecular pathway between two neurotransmitter receptor, dopamine and glutamate receptor, systems in order to understand the consequence of using logic gate rules between nodes, which have two possible states (active and inactive). RESULTS: The dynamical properties of this Boolean network model of the biochemical pathway shows that, the pathway is stable and that, deletion/knockout of certain biologically important nodes cause significant perturbation to this network. The analysis clearly shows that in addition to the expected components dopamine and dopamine receptor 2 (DRD2), Ca(2+) ions play a critical role in maintaining stability of the pathway. CONCLUSION: So this method may be useful for the identification of potential genetic targets, whose loss of function in biochemical pathways may be responsible for disease onset. The molecular pathway considered in this study has been implicated with a complex disorder like schizophrenia, which has a complex multifactorial etiology.
Animals↗
The interactive Web-based histology atlas system.
Molecular pathways and mechanisms underlying human cancer are frequently investigated in animal models. Studies to identify and dissect molecular pathways include the discovery of genes and their subsequent analysis in transgenic and 'knock-out' mice. A critical aspect in such investigations is the evaluation of organ integrity and histology upon the alteration or inactivation of specific genes. Results from such studies are usually published in scientific journals. However, due to print space and costs the display of large high quality images is limited. Furthermore, the printed media does not permit an easy comparison of histological images published in different journals and different years. The Internet provides a tool for the timely and inexpensive dissemination of scientific data to the research community. However, its potential for the analysis of histological images has not been explored. Here we present a web-based interactive histology atlas (http://histology.nih.gov) that permits the retrieval of annotated, high-resolution histology images via the Internet. This histology atlas also takes advantage of the interactive nature of the Internet to support the communication between different research groups. As an outline forum this atlas provides the framework to evaluate and understand cancer pathology, and to develop a consensus between veterinary and human pathologists.
Animals↗
Molecular genetics of human hypertension.
EH (essential hypertension) is a major public health problem in many countries due to its high prevalence and its association with coronary heart disease, stroke, renal disease, peripheral vascular disease and other disorders. Epidemiological studies have demonstrated that EH is heritable. Owing to the fact that blood pressure is controlled by cardiac output and total peripheral resistance, many molecular pathways are believed to be involved in the disease. In this review, recent genetic studies investigating the molecular basis of EH, including different molecular pathways, will be highlighted.
Chromosome Mapping↗
MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits.
Excessive inflammation is becoming accepted as a critical factor in many human diseases, including inflammatory and autoimmune disorders, neurodegenerative conditions, infection, cardiovascular diseases, and cancer. Cerebral ischemia and neurodegenerative diseases are accompanied by a marked inflammatory reaction that is initiated by expression of cytokines, adhesion molecules, and other inflammatory mediators, including prostanoids and nitric oxide. This review discusses recent advances regarding the detrimental effects of inflammation, the regulation of inflammatory signalling pathways in various diseases, and the potential molecular targets for anti-inflammatory therapy. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases that mediate fundamental biological processes and cellular responses to external stress signals. Increased activity of MAPK, in particular p38 MAPK, and their involvement in the regulation of the synthesis of inflammation mediators at the level of transcription and translation, make them potential targets for anti-inflammatory therapeutics. Inhibitors targeting p38 MAPK and JNK pathways have been developed, and preclinical data suggest that they exhibit anti-inflammatory activity. This review discusses how these novel drugs modulate the activity of the p38 MAPK and JNK signalling cascades, and exhibit anti-inflammatory effects in preclinical disease models, primarily through the inhibition of the expression of inflammatory mediators. Use of MAPK inhibitors emerges as an attractive strategy because they are capable of reducing both the synthesis of pro-inflammatory cytokines and their signalling. Moreover, many of these drugs are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disease.
Anti-Inflammatory Agents↗
Colorectal neoplasia in ulcerative colitis-recent advances.
It is recognized that ulcerative colitis (UC) predisposes to the development of colorectal adenocarcinoma (CRC), and the molecular pathway for this process differs from that for sporadic CRCs. However, several important details regarding the risk factors for and the molecular changes underlying UC-related colorectal carcinogenesis have only come to light lately. First, recent data suggest environmental factors related to long-standing inflammation contribute more to this increased cancer risk than an inherited susceptibility. Second, molecular changes that may represent the first steps in the development of neoplasia are being increasingly identified in non-dysplastic, colitic mucosa. Third, there is now good evidence suggesting that UC-related CRC may develop along more than one molecular pathway. These emerging data will hopefully contribute to attempts to prevent the development of UC-related CRC, e.g. through refining surveillance programmes. Details of the molecular heterogeneity of UC-related dysplasia and CRC may also help develop reliable tools for diagnosing the former and for predicting the behaviour of the latter. Finally, there is increasing awareness of non-epithelial colorectal malignancies which are associated with UC and may potentially increase in incidence with changes in the medical management of this inflammatory disease.
Adenocarcinoma↗
Cellular and molecular neurosurgery: pathways from concept to reality--part I: target disorders and concept approaches to gene therapy of the central nervous system.
Recent advances in cellular and molecular biology and better understanding of genetic and biochemical bases of different central nervous system (CNS) disorders have made gene therapy of the CNS a realistic goal. Concept approaches for gene therapy of CNS disorders are reviewed and include the following: 1) gene replacement with a single normal allele to correct the inherited global neurodegenerative disorders, such as enzyme deficiencies; 2) brain repair to restore the function of a particular subset of cells that were lost because of a neurodegenerative process; 3) gene therapy of brain tumors; and 4) gene therapy of stroke. Techniques of viral vector-mediated CNS transfer of a therapeutic gene, transplantation of genetically modified cells, fetal embryonic implantation and/or implantation of genetically engineered neural progenitor cells, and production of a specific enzyme, neurotransmitter, and/or growth factor are discussed with respect to the therapeutic potential for global and localized CNS neurodegenerative disorders and stroke. Transfection of the CNS tumor cells with the drug susceptibility ("suicide") gene and/or "toxic" gene and antisense strategies and a concept of adoptive immunotherapy of brain tumors are also discussed. Other approaches, such as transfer of drug-resistant genes and monoclonal antibody gene transfer, are briefly discussed. In addition to summarizing current principles of gene therapy for several groups of CNS disorders, the issues that remain to be resolved in clinical reality, such as delivery of the genetic material and regulation of the cellular expression of the transgene, and the negatives associated with the concepts of gene therapy, such as transient gene expression, toxicity of viral proteins, drawbacks of antisense therapy, and the problem of immune response to the transfected protein, have been also identified.
Animals↗
The molecular control of upper extremity development: implications for congenital hand anomalies.
As the molecular aspects of limb development are being unraveled, more of the congenital anomalies seen by hand surgeons in the clinical setting will have an identifiable molecular basis. The majority of the data available regarding the molecular development of the upper extremity have come from experimental animal studies, specifically the mouse and chicken. These findings are being discovered by either direct surgical and molecular manipulation of the developing limb or by production of mice deficient in specific genes. Relatively few specific human mutations that cause limb abnormalities have been identified. Hand surgeons should be aware of the basic molecular pathways controlling limb development because they are in a unique position to be able to identify patients with such deformities. In turn, detailed clinical descriptions of congenital anomalies affecting the upper extremity will advance the understanding of the cellular events controlled by the molecular pathways of limb development. This review describes the general molecular basis of limb development and correlates it with disease processes affecting the upper extremity.
Animals↗
Genetic and epigenetic alterations of tumor suppressor and tumor-related genes in gastric cancer.
Both genetic and epigenetic alterations of tumor suppressor and tumor-related genes involved in the pathogenesis of gastric cancer are reviewed here, and molecular pathways of gastric carcinogenesis are proposed. Gastric carcinomas are believed to evolve from native gastric mucosa or intestinal metaplastic mucosa that undergoes genetic and epigenetic alterations involving either the suppressor pathway (defects in tumor suppressor genes) or mutator pathway (defects in DNA mismatch repair genes). Methylation of E-cadherin in native gastric mucosa results in undifferentiated carcinomas (suppressor pathway), while methylation of hMLHI results in differentiated foveolar-type carcinomas (mutator pathway). The majority of differentiated gastric carcinomas however, arise from intestinal metaplastic mucosa and exhibit structural alterations of tumor suppressor genes, especially p53. They appear to be related to chronic injury, perhaps due to Helicobacter pylori infection. Approximately 20% of differentiated carcinomas (ordinary-type) have evidence of mutator pathway tumorigenesis. Mutations of E-cadherin are mainly involved in the progression of differentiated carcinomas to undifferentiated tumors. The molecular pathways of gastric carcinogenesis depend on the histological background, and gastric carcinomas show distinct biological behaviors as a result of discernible cellular genetic and epigenetic alterations.
Animals↗
Selective cancer cell apoptosis induced by FTY720; evidence for a Bcl-dependent pathway and impairment in ERK activity.
BACKGROUND: FTY720 is a unique immunosuppressant that induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. We conducted the present study to investigate its anticancer effect and molecular pathway in inducing apoptosis using murine breast cancer models. MATERIALS AND METHODS: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and cell growth assay. FTY720-induced apoptosis was determined by electron microscopy and DNA electrophoresis, and its molecular pathway was evaluated by Western blot analysis. We then tested in vivo the effect of this agent using two murine breast cancer models. RESULTS: FTY720 treatment induced selective cancer cell apoptosis in vitro at a concentration of less than 10 microM. In vivo tumor growth was significantly prevented with induction of apoptosis in both models without any severe systemic adverse reactions. The evaluation of intracellular protease activity demonstrated that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway. Inhibition of extracellular signal-regulated kinase (ERK) activity may be involved in its underlying mechanism of action. CONCLUSION: FTY720 may be a promising candidate for a new anticancer therapy, which potentially induces selective apoptosis in cancer cells.
Animals↗
Prognostic impact of molecular markers in a series of 220 primary glioblastomas.
BACKGROUND: In contrast to oligodendrogliomas, molecular predictors of prognosis have not been consistently found in glioblastomas. However, genetic studies show that glioblastomas consist of several genetic subtypes and raise the possibility that molecular alterations could be predictive of survival. METHODS: A search for loss of heterozygosity (LOH) on chromosome 1p, 9p, 10q, 19q, EGFR (epidermal growth factor receptor), CDK4, and MDM2 (mouse double minute) amplifications, CDKN2A (INK4A/ARF) homozygous deletions, p53 expression, was performed in a series of 220 primary glioblastomas. The molecular alterations were then correlated with each other to identify distinct molecular pathways and with clinical parameters and the course of the disease to identify prognostic markers. RESULTS: Nonrandom associations were found between EGFR amplification and LOH10q, LOH9p, and INK4A/ARF deletion, LOH1p and LOH19q, and MDM2 and CDK4 amplification, whereas mutual exclusions were found between p53 expression and EGFR amplification, LOH 9p/INK4A/ARF homozygous deletion, and MDM2 and CDK4 amplification. Age (P = 4.10(-5)) and performance status (P = .003) were the main predictors of outcome. In contrast, molecular markers were of limited impact: MDM2 amplification correlated with poor outcome on both univariate and multivariate analysis (P = .01) and EGFR amplification with good prognosis on multivariate analysis (P = .02). CONCLUSION: Despite their limited prognostic impact, the genetic markers investigated here outline distinct molecular pathways involved in glioblastoma tumorigenesis and warrant broader molecular screening.
Adolescent↗
The molecular biology of laryngeal cancer.
Novel techniques have led to the discovery of many genes and gene products important in the development of HNSC and laryngeal cancer. Tumor suppressive genes and oncogenes have been identified, and many of their roles have been elucidated in a genetic progression model. As these molecular pathways become better understood, the information obtained will increasingly be used to guide patient therapy. Specifically, advances will probably be made in (1) molecular characterization of steps leading to laryngeal cancer; (2) molecular screening, staging, and surveillance; (3) molecularly based therapy, including gene transfer and small molecule therapy directed at specific molecular pathways involved in neoplasia; and (4) characterization of patients who are at high risk for laryngeal cancer. In the final analysis, however, smoking cessation for those at risk for head and neck cancer would have greater effect than all these efforts combined.
Carcinoma, Squamous Cell↗
22q11 deletion syndrome: a review of some developmental biology aspects of the cardiovascular system.
The morphology and molecular genetics of the 22q11 deletion syndrome cardiovascular anomalies are reviewed. Special emphasis is given to TBX1, recently identified and considered to be the potential key gene for this clinical syndrome. The TBX1 downstream molecular pathways modulating the normal development of the pharyngeal apparatus are also discussed, and emphasis is given to the possible, equally fundamental role of downstream molecular pathway disruption in causing the clinical 22q11 deletion phenotype features.
Animals↗
TabBO: a model reflecting common molecular features of androgen-independent prostate cancer.
We established two human prostate cancer cell lines, MDA PCa 2a and MDA PCa 2b, the TabBO model system, that reflect common features of human androgen-independent prostate cancer that are not present in other model systems: bone origin, prostate-specific antigen production, androgen receptor expression, and androgen sensitivity. We therefore hypothesized that molecular pathways in our model system reflect common alterations responsible for the progression of a subset of human prostate cancer. Progression to androgen independence has been hypothesized to be largely associated with impairment of the regulation of cell growth or apoptosis of prostate cancer cells. Therefore, in this study, we examined molecular markers known or suspected to be important in prostate cancer progression and key regulators of cell growth and apoptosis: p53, p21WAF1/CIP1, Bcl-2, Bax, retinoblastoma (Rb), and p16INK4A/MITS1. We analyzed the expression of these markers in the cell lines, their tumor of origin, and tumors derived from the cell lines by s.c. inoculation into nude mice. DNA sequencing of the entire open reading frames of the p53 and p21 genes revealed no mutations. Additionally, accumulation of the p53 protein was not found by Western blot analysis, nor was overexpression of the Bcl-2 oncoprotein detected. Bax expression was detected in MDA PCa 2a cells, whereas it was absent in MDA PCa 2b. Rb and p16 protein expression was normal as measured by both Western blot and immunochemical analyses. Immunohistochemical studies of p53, p21, Bcl-2, and Rb in both samples from the original human cancer from which the lines were derived and mouse xenografts derived from the lines revealed similar levels of protein. These results are consistent with reports indicating that 40-50% of bone metastases of prostate cancer have wild-type p53, 50-70% do not overexpress the Bcl-2 protein, and mutations in the p21 gene are rare. Therefore, we conclude that MDA PCa 2a and MDA PCa 2b reflect molecular pathways in a common subset of human androgen-independent prostate cancer and that important molecular players in apoptosis (namely, p53 and Bcl-2) seem to be intact in this subset of androgen-independent prostate cancer. Understanding the signal-transduction pathways operating in these cell lines may help to identify therapeutic targets for prostate cancer.
Androgens↗
Apoptosis in the myocardium: much is still expected.
Apoptosis continues to be a controversial concept and subject of debate among scientists regarding its value as the basis for new therapeutic strategies. Today, it is widely accepted that the death of cardiac myocytes under a variety of conditions appears to be apoptotic based on a variety of criteria. However, the significance of these observations and how the insights into apoptotic molecular pathways may provide novel therapeutic targets remains to be determined. It is important to reconsider the pertinent underlying mechanisms of apoptosis regulation, and how these molecular pathways may be viewed in the functioning, intact heart. This knowledge can be applied in pursuit of practical goals in a search for new ways to prevent myocardial damage following such injuries as ischaemia/reperfusion or exposure to cardiotoxic drugs. Although recent literature contains reports of positive findings, there has not yet been a rigorous application of the model of apoptosis in the myocardium, and the potential for development of new therapeutic strategies is not yet understood.
Animals↗
Multistep and multifactorial carcinogenesis: when does a contributing factor become a carcinogen?
Our greatest successes in fighting cancer derive from the identification and removal or inactivation of carcinogenic substances, and from the identification and removal of pre-malignant lesions. In comparison, our successes at treating already formed malignancies have been minimal. Therefore, emphasis should be put in identifying and removing pre-malignant lesions, and in the identification and removal of those agents that cause or contribute to cancer development. It is important to target initiators, co-carcinogens and promoters, since by removing any one of them, tumor growth may be prevented. Identification of these agents is difficult. Epidemiological studies largely study cancer after it has occurred. It would be preferable to identify potential carcinogenic substances at an earlier stage before they have caused a large number of malignancies and thus become identifiable by epidemiology. During the past three decades, we have accumulated an impressive amount of evidence concerning molecular pathways that when altered contribute to malignant growth. It is time that we start applying this knowledge to the identification of human carcinogens. Here, we review the molecular changes that are required for carcinogenesis and propose some criteria that, in the absence of epidemiological evidence, can be used to identify agents that cause or contribute to human cancer development. In the absence of epidemiological evidence, a given agent should be considered a human carcinogen when: (1) the agent causes or contributes to the development of tumors in animals that are of the same type as those tumors associated with exposure to the agent in humans; (2) the agent transforms or contributes to the transformation of human cells in culture and these cells are of the same type from which associated human malignancies arise; (3) there is molecular evidence that the agent interferes with one or more key molecular pathways in human cells which leads to the formation of human cancer.
Animals↗
Microbial degradation of organophosphorus xenobiotics: metabolic pathways and molecular basis.
Organophosphorus (OP) xenobiotics are used worldwide as pesticides and petroleum additives. OP compounds share the major portion of the pesticide market globally. Owing to large-scale use of OP compounds, contaminations of soil and water systems have been reported from all parts of the world. OP compounds possess very high mammalian toxicity and therefore early detection and subsequent decontamination and detoxification of the polluted environment is essential. Additionally, about 200,000 tons of extremely toxic OP chemical warfare agents are required to be destroyed by 2007 under Chemical Warfare Convention (1993). Chemical and physical methods of decontamination are not only expensive and time-consuming, but also in most cases they do not provide a complete solution. These approaches convert compounds from toxic into less toxic states, which in some cases can accumulate in the environment and still be toxic to a range of organisms. Bioremediation provides a suitable way to remove contaminants from the environment as, in most of the cases, OP compounds are totally mineralized by the microorganisms. Most OP compounds are degraded by microorganisms in the environment as a source of phosphorus or carbon or both. Several soil bacteria have been isolated and characterized, which can degrade OP compounds in laboratory cultures and in the field. The biochemical and genetic basis of microbial degradation has received considerable attention. Several genes/enzymes, which provide microorganisms with the ability to degrade OP compounds, have been identified and characterized. Some of these genes and enzymes have been engineered for better efficacy. Bacteria capable of complete mineralization are constructed by transferring the complete degradation pathway for specific compounds to one bacterium. In the present article, we review microbial degradation and metabolic pathways for some OP compounds. The biochemical and molecular basis of OP degradation by microbes and the evolution and distribution of genes/enzymes are also reviewed. This article also examines applications and future use of OP-degrading microbes and enzymes for bioremediation, treatment of OP poisoning, and as biosensors.
Aryldialkylphosphatase↗
The ethylene gas signal transduction pathway: a molecular perspective.
The gaseous hormone ethylene induces diverse effects in plants throughout their life cycle. Ethylene response is regulated at multiple levels, from hormone synthesis and perception to signal transduction and transcriptional regulation. As more genes in the ethylene response pathway are cloned and characterized, they illustrate the precision with which signaling can be controlled. Wounding, pathogenic attack, flooding, fruit ripening, development, senescence, and ethylene treatment itself induce ethylene production. Ethylene binding to receptors with homology to two-component regulators triggers a kinase cascade that is propagated through the CTR1 Raf-like kinase and other components to the nucleus. Activation of the EIN3 family of nuclear proteins leads to induction of the relevant ethylene-responsive genes via other transcription factors, eliciting a response appropriate to the original stimulus.
Amino Acid Oxidoreductases↗