Mitochondria and Cancer

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Bioinorganic Chemistry of Alzheimer’s Disease

The immense majority of genes are alternatively spliced and there are many isoforms specifically associated with cancer progression and metastasis. The splicing pattern of specific isoforms of numerous genes is altered as cells move through the oncogenic process of gaining proliferative capacity, acquiring angiogenic, invasive, antiapoptotic and survival properties, becoming free from growth factor dependence and growth suppression, altering their metabolism to cope with hypoxia, enabling them to acquire mechanisms of immune escape, and as they move through the epithelial-mesenchymal and mesenchymal-epithelial transitions and metastasis. Each of the 'hallmarks of cancer' is associated with a switch in splicing, towards a more aggressive invasive cancer phenotype. The choice of isoforms is regulated by several factors (signaling molecules, kinases, splicing factors) currently being identified systematically by a number of high-throughput, independent and unbiased methodologies. Splicing factors are de-regulated in cancer, and in some cases are themselves oncogenes or pseudo-oncogenes and can contribute to positive feedback loops driving cancer progression. Tumour progression may therefore be associated with a coordinated splicing control, meaning that there is the potential for a relatively small number of splice factors or their regulators to drive multiple oncogenic processes. The understanding of how splicing contributes to the various phenotypic traits acquired by tumours as they progress and metastasise, and in particular how alternative splicing is coordinated, can and is leading to the development of a new class of anticancer therapeutics-the alternative-splicing inhibitors.

Hallmarks of alternative splicing in cancer.

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.

https://www.mdpi.com/2218-273X/9/11/735/pdf

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements.

Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients.

Several pharmacological agents acting on monoamine neurotransmission are used for the management of mental illnesses. Regulation of PI3K/AKT and GSK3 pathways may constitute an important signaling center in the subcellular integration of the synaptic neurotransmission. The pathways also modulate neuronal cell proliferation, migration, and plasticity. There are evidences to suggest that inflammation of neuron contributes to the pathology of depression. Inflammatory activation of neuron contributes to the loss of glial elements, which are consistent with pathological findings characterizing the depression. A mechanism of anti-inflammatory reactions from antidepressant medications has been found to be associated with an enhancement of heme oxygenase-1 expression. This induction in brain is also important in neuroprotection and neuroplasticity. As enzymes involved in cell survival and neuroplasticity are relevant to neurotrophic factor dysregulation, the PI3K/AKT/GSK3 may provide an important signaling for the neuroprotection in depression. In this paper, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells in mental illnesses.

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Roles of pi3k/akt/gsk3/mtor pathway in cell signaling of mental illnesses

Alzheimer’s disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3β pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3β pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD.

/pdf/dietary-regulation-of-pi3k-akt-gsk-3b-pathway-in-alzheimer-s-41zgcfu9z1.pdf

Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome, which represents a range of fatty liver diseases associated with an increased risk of type 2 diabetes. Molecular mechanisms underlying how to make transition from simple fatty liver to nonalcoholic steatohepatitis (NASH) are not well understood. However, accumulating evidence indicates that deregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in hepatocytes is a common molecular event associated with metabolic dysfunctions including obesity, metabolic syndrome, and the NAFLD. A tumor suppressor PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Molecular studies in the NAFLD support a key role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis, and fibrosis. We review recent studies on the features of the PTEN and the PI3K/AKT pathway and discuss the protein functions in the signaling pathways involved in the NAFLD. The molecular mechanisms contributing to the diseases are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies for a condition.

/pdf/roles-for-pi3k-akt-pten-pathway-in-cell-signaling-of-4m9ooop3x6.pdf

Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease

Psychiatric illnesses may be qualified to the cellular impairments of the function for survival or death in neurons, which may consequently appear as abnormalities in the neuroplasticity. The molecular mechanism has not been well understood, however, it seems that PI3K, AKT, GSK3, and their downstream molecules have crucial roles in the pathogenesis. Through transducing cell surviving signal, the PI3K/AKT/GSK3 pathway may organize an intracellular central network for the action of the synaptic neuroplasticity. In addition, the pathways may also regulate cell proliferation, cell migration, and apoptosis. Several lines of evidence have supported a role for this signaling network underlying the development and treatment for psychiatric illnesses. Indeed, the discovery of molecular biochemical phenotypes would represent a breakthrough in the research for effective treatment. In this review, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells. This study may provide novel insights on the mechanism of mental disorder involved in psychiatric illnesses and would open future opportunity for contributions suggesting new targets for diagnostic and/or therapeutic procedures.

https://www.mdpi.com/2079-9721/7/1/22/pdf

Roles of PI3K/AKT/GSK3 Pathway Involved in Psychiatric Illnesses

Accumulating evidence has revealed that thePI3K/AKT/PTENpathway acts as a pivotal determinant of cell fate regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. NADPH oxidase (NOX) family of enzymes generates the ROS. The regulation of NOX enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. Cells are continuously exposed to the ROS, which represent mutagens and are thought to be a major contributor to several diseases including cancer and aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, the roles of oxidative stress in PI3K/AKT/PTEN signaling are summarized with a focus on the links between the pathways and NOX protein in several diseases including cancer and aging.

https://jeffreydachmd.com/wp-content/uploads/2014/06/NOX-Protein-in-Diseases_AD-2014-Matsuda.pdf

Yasuko Kitagishi

Papers

Roles of pi3k/akt/gsk3/mtor pathway in cell signaling of mental illnesses

Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease

Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease

Roles of PI3K/AKT/GSK3 Pathway Involved in Psychiatric Illnesses

Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases.