Alterations In Molecular Mechanisms Research Articles

THE EFFECT OF ALKALOID SONGORINE ON MITOCHONDRIAL RESPIRATORY RATE AND OXIDATIVE PHOSPHORYLATION PROCESS UNDER NORMAL AND SHORT-TERM STRESS

Stress conditions adversely affect normal physiological functions, resulting in cellular dysfunctions and alterations in molecular mechanisms. Mitochondria, multifunctional organelles within cells, play crucial roles across various aspects of cell physiology, beyond their role in ATP synthesis. Among the biologically active substances, the diterpene alkaloid songorine has an activating effect on the rate of respiration and on the processes of oxidative phosphorylation of normal and stress-induced mitochondria in vitro.

Abstract 3545: Alterations of molecular mechanisms in newly selected 5-fluorouracil resistant pancreatic cancer cell line and the effect of biochanin A thereon

Abstract Resistance to drugs is one of the major contributor to the high mortality rate of pancreatic cancer. The molecular mechanisms of pancreatic cancer drug resistance are not well understood. We generated and characterized a 5FU resistant pancreatic cancer cell line (AsPC1/R). 5FU resistant pancreatic cancer cells (AsPC1/R) were selected with the increasing concentration of the drug till 6-fold resistance was achieved. Our dose response studies show that the resistant cells were cross-resistant to the gefitinib; however, the sensitivity to gemcitabine was not altered. Western blot analysis shows lower level of EGFR in the AsPC1/R as compared to AsPC1 cells. In addition, our results indicate that the resistant cells have high levels of activated Erk 1 and Akt. Levels of c-fos and c-jun in the nuclear fraction were upregulated in the resistant cells. Furthermore, invasive mechanisms such as uPAR and MMP activity are upregulated in the AsPC1/R cells compared to the parent cells. We also determined the effect of biochanin A on 5FU resistance and found that it reverses the 5FU resistance in AsPC1/R cells. Our previous studies have shown that biochanin A reduces the levels of thymidylate synthase and the levels of activated Erk and Akt. We conclude that biochanin A may overcome 5FU resistance in pancreatic cancer and could be used in combination with other chemotherapeutic agents in treating pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3545.

Increased CRMP2 phosphorylation is observed in Alzheimer's disease; does this tell us anything about disease development?

Collapsin response mediator protein-2 (CRMP2) was recently identified as a physiological substrate for GSK3 and Cdk5, two protein kinases suggested to exhibit greater activity in Alzheimer's disease (AD). Indeed, phosphorylation of CRMP2, at the residues targeted by GSK3 and Cdk5, is relatively high in cortex isolated from human AD brain, as well as in the brains of animal models of AD, while phospho-CRMP2 is found in neurofibrillary tangles. In mouse models of AD, increased phosphorylation occurs prior to pathology. Although CRMP2 has no known enzymatic activity, a great deal of information is appearing on its importance in neuronal development and polarity, as well as in axon growth and guidance. In this mini-review, we examine what is known about CRMP2 function, how that is controlled by phosphorylation, what alterations in molecular mechanisms could lead to the abnormally high CRMP2 phosphorylation in AD, and whether this is likely to be specific to AD or occur in other forms of neurodegeneration. This will include discussion of the evidence for increased GSK3 or Cdk5 activity, for decreased phosphatase activity, or the upregulation of other CRMP2 protein kinases in AD. Importantly, we will compare the processes that may contribute to increased CRMP2 phosphorylation with those known to increase tau hyperphosphorylation in AD, and whether these are likely to be part of disease development or a useful early marker for AD.

Movement disorders: Classifications

Movement disorders (ataxia, dystonic disorders, gait disorders, Huntington disease, myoclonus, parkinsonism, spasticity, tardive dyskinesia, tics and tremor) are clinically, pathologically and genetically heterogeneous and are characterized by impairment of the planning, control or execution of movement. Current classifications of these disorders have inherent shortcomings due to the complex nature of movement disorders and the lack of diagnostic tests for the majority. Undiscriminating terminology, as well as the clinical, pathological and genetic heterogeneity, further complicate the development of comprehensive categorizations. Modern classification schemes tend to focus on clinical, pathological or genetic/molecular criteria, but more recent attempts have been made to integrate across these levels. From a historical perspective, two 'golden ages' have shaped the current and evolving classification schemes: (1) the definition of clinical pathological entities in the early twentieth century and (2) the application of molecular neurogenetics in the past 10-15 years. However, the classification of movement disorders on clinical grounds (according to age at onset, distribution of symptoms, disease course, provoking factors and therapeutic response) remains one of the most useful modes of categorization. Postmortem criteria have been employed to distinguish between degenerative and nondegenerative disorders, and specific hallmarks may be required to establish or confirm a diagnosis. Genetic features used for classification purposes include mode of inheritance and molecular genetic data, such as linkage to a known gene locus or identification of a specific genetic defect. A final classification scheme is based on alterations in molecular mechanisms (e.g. trinucleotide expansions) or protein function (e.g. channelopathies). Despite recent advances, it may not be possible to develop the 'ultimate' classification of movement disorders, and different patterns of lumping and splitting may be useful for the clinician, the pathologist or the geneticist/molecular biologist. Furthermore, certain individual cases with unique features may not fit into any particular category. Continued research by both clinicians and basic scientists is necessary in order to refine and redefine classification schemes of movement disorders.

Inactivation of Cyclin-Dependent Kinase Inhibitor Genes and Development of Human Acute Leukemias

A large body of evidence has definitely demonstrated that cancer development and/or progression is strictly linked to alterations of molecular mechanisms controlling the cell division cycle. In particular, those aberrations which cause a shortening of G1 phase length and a deregulated S phase entry seem to be very important. Two main tumor suppressor loci, involved in the cell cycle regulation, are frequently altered in human tumors. One is located on 13q14 chromosome and includes the gene coding pRb protein while the other is located on 9p21 chromosome and involves two genes, namely p16INK4A and p15INK4B which belong to the same gene family. While RB1 gene is scarcely altered in hematological tumors, the putative tumor suppressor gene(s) on 9p21 appear(s) to be frequently inactivated in some subtypes of cancers derived from hematopoietic tissues.This manuscript will review the main biochemical aspects of the cell division cycle with major emphasis devoted to the findings regarding the recently characterized small proteic mitotic inhibitors and to their possible role in cancer formation. Particular attention will be paid to the data concerning the incidence of p16INK4A (and p15INK4B) gene(s) inactivation in human acute lymphoblastic leukemias. Indeed, such gene(s) seems to be the main, and until now the unique, tumor suppressor gene consistently altered in this acute hematological cancer diseases. Finally, future directions in studies on the connection between cell cycle control and leukemogenesis will be analyzed.