Akari Minami

Functions and characteristics of PINK1 and Parkin in cancer.

Most of the Parkinson disease (PD) linked genes are also associated with cancers. In particular, phosphatase and tensin homologue-induced kinase 1 (PINK1) and Parkin, both of which are involved in recessively inherited familial forms of PD linked to mitochondrial dysfunction, appear to be abnormally expressed in cancers. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. Although PD and cancer are obviously disparate human disorders, there is an evidence for low cancer rates in patients with PD. The relationship between cancer rates and PD might be related to the involvement of common pathways in both diseases. This paper provides a concise overview on the cellular functions of the PINK1 and Parkin.

PI3K/AKT/PTEN pathway as a target for Crohn's disease therapy (Review)

The pathogenesis of inflammatory bowel disease (IBD), including Crohns disease, is a subject of increasing interest. Loss-of-function mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are strong genetic factors linked to Crohns disease, which eventually leads to an excessive mucosal inflammatory response directed against components of normal gut microbiota. Reactive oxygen species (ROS) play an important role in inflammation processes, as well as in transduction of signals from receptors for several cytokines, such as tumor necrosis factor α (TNFα). ROS activate nuclear factor-κB (NF-κB) via IκB kinase (IKK) through the PI3K/AKT/PTEN pathway. Therefore, this pathway is recognized to play a key role in Crohns disease. Loss of function has been demonstrated to occur as an early event in a wide variety of diseases. Given this prevalent involvement in a number of diseases, the molecular development that modulates this pathway has been the subject of several studies. In addition, it has been the focus of extensive research and drug discovery activities. A better understanding of the molecular assemblies may reveal novel targets for the therapeutic development against Crohns disease.

BRCA1 and p53 Tumor Suppressor Molecules in Alzheimer’s Disease

Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer’s disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer’s disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer’s disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field.

Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair

Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.

Roles of PTEN with DNA Repair in Parkinson's Disease

Oxidative stress is considered to play key roles in aging and pathogenesis of many neurodegenerative diseases such as Parkinson’s disease, which could bring DNA damage by cells. The DNA damage may lead to the cell apoptosis, which could contribute to the degeneration of neuronal tissues. Recent evidence suggests that PTEN (phosphatase and tensin homolog on chromosome 10) may be involved in the pathophysiology of the neurodegenerative disorders. Since PTEN expression appears to be one dominant determinant of the neuronal cell death, PTEN should be a potential molecular target of novel therapeutic strategies against Parkinson’s disease. In addition, defects in DNA damage response and DNA repair are often associated with modulation of hormone signaling pathways. Especially, many observations imply a role for estrogen in a regulation of the DNA repair action. In the present review, we have attempted to summarize the function of DNA repair molecules at a viewpoint of the PTEN signaling pathway and the hormone related functional modulation of cells, providing a broad interpretation on the molecular mechanisms for treatment of Parkinson’s disease. Particular attention will be paid to the mechanisms proposed to explain the health effects of food ingredients against Parkinson’s disease related to reduce oxidative stress for an efficient therapeutic intervention.

Neuron Membrane Trafficking and Protein Kinases Involved in Autism and ADHD

A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention.

Function of α-synuclein and PINK1 in Lewy body dementia (Review)

α-Synuclein (α-syn) is the major protein component of Lewy bodies, a key pathological characteristic of the degenerating brain. The misfolding and aggregation of α-syn is associated with both the idiopathic and familial forms of Parkinsons disease (PD) and Lewy body dementia (LBD). However, the function of α-syn is poorly understood, as it shows both neurotoxic and neuroprotective activities. Mutations in phosphatase and tensin homologue-induced putative kinase 1 (PINK1) also cause recessively inherited PD. Studies support the notion of neuroprotective roles for PINK1, as it protects cells from damage-induced mitochondrial dysfunction, oxidative stress and cell apoptosis. PINK1 plays an essential role in mitochondrial quality control and its homeostasis is maintained through mitochondrial stabilization. The α-syn aggregation is linked to various aspects of mitochondrial dysfunction and PINK1-related mitophagy. Determination of the molecular pathways that lead to α-syn oligomerization and further aggregation may be the basis for the successful design and development of treatments for these neurodegenerative diseases. The present review summarizes the function of PINK1 underlying α-syn aggregation and the mechanisms through which mitochondrial dysfunction plays a role in this process.

Atherosclerosis and tumor suppressor molecules (review).

Atherosclerosis, the major cause of heart attack and stroke, is a chronic inflammatory disease characterized by the formation of atherosclerotic plaque. Oxidized low-density lipoprotein through increased oxidative stress has been identified as one of the primary factors responsible for atherogenesis. Cell proliferation and death are key processes in the progression of atherosclerosis. The oxidative environment in areas of lipid accumulation is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage and levels of DNA repair are reduced during dietary lipid lowering. The tumor suppressor molecules play a pivotal role in regulating cell proliferation, DNA repair and cell death, which are important processes in regulating the composition of atherosclerotic plaque. Accordingly, in this review, we discuss the fundamental role of tumor suppressor molecules in regulating atherogenesis. In particular, we discuss how tumor suppressor molecules are activated in the complex environment of atherosclerotic plaque, and regulate growth arrest, cell senescence and the apoptosis of vascular smooth muscle cells, which may protect against the progression of atherosclerosis. In addition, we discuss promising alternatives to the use of medications (such as statin) against atherosclerosis, namely diet, with the use of plant-derived supplements to modulate the expression and/or activity of tumor suppressor molecules. We also summarize the progress of research made on herbs with a focus on the modulatory roles of tumor suppressors, and on the molecular mechanisms underlying the prevention if atherosclerosis, supporting designs for further research in this field.

Certain Diet and Lifestyle May Contribute to Islet β-cells Protection in Type-2 Diabetes via the Modulation of Cellular PI3K/AKT Pathway.

PI3K/AKT pathway has been shown to play a pivotal role on islet β-cell protection, enhancing β-cell survival by stimulating cell proliferation and inhibiting cell apoptosis. Accordingly, this pathway appears to be crucial in type-2 diabetes. Understanding the regulations of this pathway may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances on the involvement of the PI3K/AKT pathway in hypothetical intra-cellular signaling of islet β-cells. As recent findings may show the nutritional regulation of the survival pathway in the islet β-cells through activation of the PI3K/AKT pathway, we also review studies on the features of several diets, correlated lifestyle, and its signaling pathway involved in type-2 diabetes. The molecular mechanisms contributing to the disease are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies against a condition of the disease.

Effective PI3K modulators for improved therapy against malignant tumors and for neuroprotection of brain damage after tumor therapy (Review)

Due to the key role in various cellular processes including cell proliferation and cell survival on many cell types, dysregulation of the PI3K/AKT pathway represents a crucial step of the pathogenesis in many diseases. Furthermore, the tumor suppressor PTEN negatively regulates the PI3K/AKT pathway through its lipid phosphatase activity, which is recognized as one of the most frequently deleted and/or mutated genes in human cancer. Given the pervasive involvement of this pathway, the development of the molecules that modulate this PI3K/AKT signaling has been initiated in studies which focus on the extensive effective drug discovery. Consequently, the PI3K/AKT pathway appears to be an attractive pharmacological target both for cancer therapy and for neurological protection necessary after the therapy. A better understanding of the molecular relations could reveal new targets for treatment development. We review recent studies on the features of PI3K/AKT and PTEN, and their pleiotropic functions relevant to the signaling pathways involved in cancer progress and in neuronal damage by the therapy.