High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid β-protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aβ1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aβ1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aβ1-42 were significantly greater than those of LMW-Aβ1-42. Therapeutic reduction of HMW-Aβ1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage

Usefulness Differs Between the Visual Assessment and Specific Binding Ratio of 123I-Ioflupane SPECT in Assessing Clinical Symptoms of Drug-Naïve Parkinson’s Disease Patients

Background: In clinical practice, assessment of the striatal accumulation in 123I-ioflupane single photon emission computed tomography (SPECT) is commonly performed calculating the specific binding ratio (SBR) for the whole striatum. On the other hand, visual assessment of striatal accumulation in the SPECT was recently established. However, correlations of visual assessment with motor and cognitive functions in Parkinson’s disease (PD) have rarely been examined. Differences in the usefulness of these assessments at clinics are uncertain.Objective: We performed this study to compare correlations of cognitive and motor functions in drug-naive PD between the SBR and visual assessment using 123I-ioflupane SPECT.Methods: Cognitive and motor assessments and 123I-ioflupane SPECT were performed in 47 drug-naïve PD patients with Mini-mental State Examination scores of ≥25. Cognitive function was assessed using the total score and 6 subscores of the Montreal Cognitive Assessment (MoCA) and 10 separate subtests of the Neurobehavioral Cognitive Status Examination (COGNISTAT). Motor function was assessed using the Hoehn and Yahr scale and Unified Parkinson’s Disease Rating Scale. Accumulation of 123I-ioflupane was determined by visual assessment based on five grades: 1, burst striatum; 2, egg-shaped; 3, mixed type; 4, eagle wing; 5, normal striatum; and by calculating SBR averaged for the bilateral striatum using the DaTView computer software commonly used in clinical practice. Each SPECT assessment was compared with each subscore for cognitive and motor assessments.Results: Spearman correlation analysis showed SBR was significantly correlated with the MoCA subscores of visuospatial function and attention, and with COGNISTAT subtests of attention. Visual assessment showed significant negative correlation with the Hoehn and Yahr scale. Mean score of postural instability in patients with visual grade of 1 was significantly higher than those in patients with visual grades of 2 and 3.Conclusion: Clinical symptoms reflected by 123I-ioflupane SPECT differ between the SBR and visual assessment. SBR reflects some cognitive functions, whereas a visual assessment grade of 1, which signifies decreased uptake of 123I-Ioflupane in the caudate nucleus, reflects postural instability. Thus, the caudate nucleus may play an important role in posture maintenance. Our results suggest that performing both assessments is of value

Eribulin Treatment Induces High Expression of miR-195 and Inactivates the Wnt/β - catenin Signaling Pathway in Triple-negative Breast Cancer

Triple-negative breast cancer （TNBC） accounts for 10-15％ of all breast cancer cases and shows a poor prognosis with 30％ distant metastasis. With few specific target molecules and ineffective hormonal and anti-HER2 treatment, an alternative therapeutic method for TNBC is urgently required. Recently, a non-taxane inhibitor of microtubule dynamics called eribulin was developed for breast cancer therapy. Eribulin induces irreversible mitotic mass formation in cancer cells during the G2-M phase, initiating apoptosis; however, the mechanism underlying this eribulin activity remains unclear. We reported previously that exposing non-basal-like （NBL） TNBC cells to eribulin increases miR-195 expression, which in turn decreases the expression of targeted Wnt3a. The present study sought to further clarify the mechanism of this antitumor effect by exploring how eribulin affects Wnt/β - catenin signaling based on miRNA expression changes in TNBC. In an NBL type of human breast cancer cell line （MDA-MB-231 cells）, we compared the expression levels of Wnt/β catenin signaling pathway proteins in cells exposed to an miR-195 mimic （cells transfected with miR-195 and in which Wnt3a expression was suppressed） and in cells exposed to eribulin. Expression levels of Wnt3a, β -catenin, and GSK-3β were measured by ELISA and observed by fluorescence immunostaining. Wnt3a and β -catenin expression was significantly lower and GSK-3β expression was significantly higher in the cells exposed to eribulin and transfected with miR-195 mimic than in the untreated controls, suggesting that eribulin inactivates the Wnt/β -catenin signaling pathway. Therefore, a novel antitumor mechanism of eribulin was determined, whereby eribulin induces high expression of miR-195 to inactivate the Wnt/β -catenin signaling pathway in NBL-type TNBC

Whole-body diffusion-weighted imaging for staging malignant lymphoma in children

CT is currently the mainstay in staging malignant lymphoma in children, but the risk of second neoplasms due to ionizing radiation associated with CT is not negligible. Whole-body MRI techniques and whole-body diffusion-weighted imaging (DWI) in particular, may be a good radiation-free alternative to CT. DWI is characterized by high sensitivity for the detection of lesions and allows quantitative assessment of diffusion that may aid in the evaluation of malignant lymphomas. This article will review whole-body MRI techniques for staging malignant lymphoma with emphasis on whole-body DWI. Furthermore, future considerations and challenges in whole-body DWI will be discussed

Cilostazol Suppresses Aβ-induced Neurotoxicity in SH-SY5Y Cells through Inhibition of Oxidative Stress and MAPK Signaling Pathway

Alzheimer’s disease (AD) is a slowly progressive form of dementia, characterized by memory impairment and cognitive dysfunction. AD is mainly characterized by the deposition of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain, along with neuronal degeneration and high levels of oxidative stress. Cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. This present study aimed to clarify the mechanism by which CSZ protects neurons from degeneration associated with Aβ(1–42). We used Aβ(1–42) to induce neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with CSZ before co-treatment with Aβ. To evaluate the effect of CSZ on oxidative stress, we examined levels of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity, mRNA expression of NOX4, and Cu/Zn-Superoxide Dismutase (SOD), as well as apoptosis biomarkers [MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), caspase-3 and -9 activities and staining of annexin V]. We also assayed the activity of mitogen-activated protein kinases (MAPK): p38 MAPK and extracellular signal-regulated kinase1/2 (ERK1/2), and biomarkers of mitochondrial function (Bcl-2 and Bax), and cyclic adenosine monophosphate response element-binding protein (CREB). Aβ-induced oxidative stress (ROS, NOX4 activity, and expression of NOX mRNA), caspase activation (caspase-3 and -9), and p38 MAPK phosphorylation were suppressed by co-treatment with CSZ, but not by ERK1/2 activation. In addition, pretreatment with CSZ suppressed Aβ-induced apoptosis and increased cell viability via suppression of Bax (a proapoptotic protein), upregulation of Bcl-2 (an antiapoptotic protein) and Cu/Zn-SOD (a superoxide scavenging enzyme), and phosphorylation of CREB. These findings suggested that CSZ could counteract neurotoxicity through multiple mechanisms, one mechanism involving the attenuation of oxidative stress by suppressing NOX activity and Nox mRNA expression in Aβ-induced neurotoxicity and another involving the anti-neurotoxic effect via the ERK1/2/phosphorylated CREB pathway

High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage.

Amyloid β-protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW-Aβ1-42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long-term potentiation (LTP). HMW-Aβ1-42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW-Aβ1-42 were significantly greater than those of LMW-Aβ1-42. Therapeutic reduction of HMW-Aβ1-42 may prevent AD progression by ameliorating direct neuronal membrane damage.-Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe-Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid β1-42 oligomers induce neurotoxicity via plasma membrane damage