The Curcumin Derivative GT863 Protects Cell Membranes in Cytotoxicity by Aß Oligomers.

In Alzheimer's disease (AD), accumulation of amyloid ß-protein (Aß) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aß has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aß-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aß oligomers (Aßo), which include high-molecular-weight (HMW) Aßo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 µM) on Aßo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca2+ ([Ca2+]i). GT863 inhibited the Aßo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca2+]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aßo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aßo exposure.

Combined Treatment with Curcumin and Ferulic Acid Suppressed the Aß-Induced Neurotoxicity More than Curcumin and Ferulic Acid Alone.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive decline. Several effective natural components have been identified for the treatment of AD. However, it is difficult to obtain conclusive evidence on the safety and effectiveness of natural components, because a variety of factors are associated with the progression of AD pathology. We hypothesized that a therapeutic effect could be achieved by combining multiple ingredients with different efficacies. The purpose of this study was thus to evaluate a combination treatment of curcumin (Cur) and ferulic acid (FA) for amyloid-ß (Aß)-induced neuronal cytotoxicity. The effect of Cur or FA on Aß aggregation using thioflavin T assay was confirmed to be inhibited in a concentration-dependent manner by Cur single or Cur + FA combination treatment. The effects of Cur + FA on the cytotoxicity of human neuroblastoma (SH-SY5Y) cells induced by Aß exposure were an increase in cell viability, a decrease in ROS and mitochondrial ROS, and repair of membrane damage. Combination treatment showed an overall higher protective effect than treatment with Cur or FA alone. These results suggest that the combined action mechanisms of Cur and FA may be effective in preventing and suppressing the progression of AD.

Correlated levels of cerebrospinal fluid pathogenic proteins in drug-naïve Parkinson's disease.

BACKGROUND AND AIM: Toxic oligomeric α-synuclein (αS; O-αS) has been suggested to play a central role in the pathogenesis of Lewy body diseases such as Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of αS, O-αS, total and phosphorylated tau, and amyloid ß 1-42 (Aß1-42) are thought to reflect the pathophysiology or clinical symptoms in PD. In this study, we examined correlations of the CSF levels of these proteins with the clinical symptoms, and with each other in drug-naïve patients with PD. METHODS: Twenty-seven drug-naïve patients with PD were included. Motor and cognitive functions were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), and Neurobehavioral Cognitive Status Examination (COGNISTAT). CSF levels of total αS, O-αS, Aß1-42, total tau and tau phosphorylated at threonine 181 (P-tau181p) were measured. CSF levels of these proteins were compared with clinical assessments from the UPDRS, MoCA and COGNISTAT using Spearman correlation analysis. Spearman correlation coefficients among CSF protein levels were also evaluated. RESULTS: CSF levels of αS were negatively correlated with UPDRS part III (motor score) (p < 0.05) and bradykinesia (p < 0.01), and positively correlated with COGNISTAT subtest of judgement (p < 0.01) and CSF levels of Aß1-42 (p < 0.001), total tau (p < 0.001) and P-tau181p (p < 0.01). Lower CSF levels of Aß1-42, total tau and P-tau181p were significantly related to worsening of some motor and/or cognitive functions. The CSF level of O-αS showed no correlation with any motor and cognitive assessments or with CSF levels of the other proteins. CONCLUSION: CSF levels of αS are correlated with some clinical symptoms and CSF levels of other pathogenic proteins in drug-naïve PD patients. These correlations suggest a central role for interaction and aggregation of αS with Aß1-42, tau, and phosphorylated tau in the pathogenesis of PD. Although O-αS has been shown to have neurotoxic effects, CSF levels do not reflect clinical symptoms or levels of other proteins in cross-sectional assessment.

Effects of All trans-Retinoic Acid on Alveolar Regeneration in Dexamethasone-Induced Emphysema Models and Its Relationship to Exposure in ICR and FVB Mice.

During the past two decades, it has been reported that treatment with all-trans-retinoic acid (ATRA) induces alveolar regeneration in rodent emphysema models. In the present study, we investigated the regeneration by ATRA at various exposure conditions in two strains of mice with induced emphysema. The emphysema model was created by postnatal administration of dexamethasone to ICR and FVB mice, which were then treated with ATRA from postnatal day 42. The regeneration was observed in ICR mice but not in FVB mice given 10 and 40 mg/kg/d ATRA for 10 d. The concentration-time profiles of ATRA in plasma and lung were similar in both strains. These results suggest that the strain difference in the regeneration by ATRA was not caused by differences in the exposure to ATRA. On the other hand, the regeneration in ICR mice was enhanced by an increase of the intraperitoneal dose in the range of 10-40 mg/kg/d for 10 d. At an intraperitoneal dose of 40 mg/kg/d, the regeneration was observed after 10 and 20 d of treatment but not after 1 to 5 d of treatment. Meanwhile, the regeneration by intraperitoneal administration of ATRA was enhanced more than that by oral administration. Exposure to ATRA during repeated intraperitoneal administration to ICR mice was higher than that in oral administration. The results suggest that the regeneration in ICR mice requires at least 10 d of treatment with ATRA and its effects depend on the exposure to ATRA in plasma, which parallels that in lung.

Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aß-Oligomer-Induced Neurotoxicity.

Amyloid ß-peptide (Aß) synthesis and deposition are the primary factors underlying the pathophysiology of Alzheimer's disease (AD). Aß oligomer (Aßo) exerts its neurotoxic effects by inducing oxidative stress and lesions by adhering to cellular membranes. Though several antidepressants have been investigated as neuroprotective agents in AD, a detailed comparison of their neuroprotection against Aßo-induced neurotoxicity is lacking. Here, we aimed to elucidate the neuroprotective effects of clinically prescribed selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants at the cellular level and establish the underlying mechanisms for their potential clinical applications. Therefore, we compared the neuroprotective effects of three antidepressants, fluoxetine (Flx), duloxetine (Dlx), and mirtazapine (Mir), by their ability to prevent oxidative stress-induced cell damage, using SH-SY5Y cells, by evaluating cell viability, generation of reactive oxygen species (ROS) and mitochondrial ROS, and peroxidation of cell membrane phospholipids. These antidepressants exhibited potent antioxidant activity (Dlx > Mir > Flx) and improved cell viability. Furthermore, pretreatment with a 5-hydroxytryptamine 1A (5-HT1A) antagonist suppressed their effects, suggesting that the 5-HT1A receptor is involved in the antioxidant mechanism of the antidepressants' neuroprotection. These findings suggest the beneficial effects of antidepressant treatment in AD through the prevention of Aß-induced oxidative stress.

Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aß-Oligomer-Induced Neuronal Injury.

Amyloid-ß (Aß) is one of the causes of Alzheimer's disease (AD), damaging nerve membranes and inducing neurotoxicity. AD is more prevalent in female patients than in male patients, and women are more susceptible to developing AD due to the decline in estrogen levels around menopause. Raloxifene, a selective estrogen receptor modulator, exhibits protective effects by activating the transmembrane G-protein-coupled estrogen receptor (GPER). Additionally, raloxifene prevents mild cognitive impairment and restores cognition. However, the influence of raloxifene via GPER on highly toxic Aß-oligomers (Aßo)-induced neurotoxicity remains uncertain. In this study, we investigated the GPER-mediated neuroprotective effects of raloxifene against the neurotoxicity caused by Aßo-induced cytotoxicity. The impact of raloxifene on Aßo-induced cell damage was evaluated using measures such as cell viability, production of reactive oxygen species (ROS) and mitochondrial ROS, peroxidation of cell-membrane phospholipids, and changes in intracellular calcium ion concentration ([Ca2+]i) levels. Raloxifene hindered Aßo-induced oxidative stress and reduced excessive [Ca2+]i, resulting in improved cell viability. Furthermore, these effects of raloxifene were inhibited with pretreatment with a GPER antagonist. Our findings suggest that raloxifene safeguards against Aßo-induced neurotoxicity by modifying oxidative parameters and maintaining [Ca2+]i homeostasis. Raloxifene may prove effective in preventing and inhibiting the progression of AD.

Ventilation improvement and evaluation of its effectiveness in a Japanese manufacturing factory.

A coronavirus disease 2019 (COVID-19) cluster emerged in a manufacturing factory in early August 2021. In November 2021, we conducted a ventilation survey using the tracer gas method. Firstly, we reproduce the situation at the time of cluster emergence and examined whether the ventilation in the office was in a condition that increased the risk of aerosol transmission. Secondly, we verified the effectiveness of the factory's own countermeasure implemented immediately after the August cluster outbreak. Furthermore, we verified the effectiveness of several additional improvement measures on the factory's own countermeasures already installed in August. Under the conditions of the cluster emergence, the air changes per hour (ACH) value was 0.73 ACH on average. The ACH value was less than 2 ACH recommended by the Ministry of Health, Labour, and Welfare, suggesting an increased risk of aerosol transmission. The factory's own countermeasures taken immediately in August were found to be effective, as the ACH value increased to 3.41 ACH on average. Moreover, it was confirmed that additional improvement measures on the factory's own countermeasures increased the ACH value to 8.33 ACH on average. In order to prevent the re-emergence of COVID-19 clusters due to aerosol infection in the office, it was found that while continuing the factory's own countermeasure, additional improvement measures should also be added depending on the number of workers in the room. In a company, it is important that workers themselves continue to take infection control measures autonomously, and confirming the effectiveness of the measures will help maintain workers' motivation. We believe it is helpful that external researchers in multiple fields and internal personnel in charge of the health and safety department and occupational health work together to confirm the effectiveness of conducted measures, such as in this case.

Bond energy analysis revisited and designed toward a rigorous methodology.

The present study theoretically revisits and numerically assesses two-body energy decomposition schemes including a newly proposed one. The new decomposition scheme is designed to make the equilibrium bond distance equivalent with the minimum point of bond energies. Although the other decomposition schemes generally predict the wrong order of the C-C bond strengths of C(2)H(2), C(2)H(4), and C(2)H(6), the new decomposition scheme is capable of reproducing the C-C bond strengths. Numerical assessment on a training set of molecules demonstrates that the present scheme exhibits a stronger correlation with bond dissociation energies than the other decomposition schemes do, which suggests that the new decomposition scheme is a reliable and powerful analysis methodology.

Agraphia of the left hand with dysfunction of the left superior parietal region without callosal lesions.

A 28-year-old right-handed man noticed weakness in his legs, three days after an ephedrine overdose. Initial brain magnetic resonance imaging showed lesions in the parietal regions bilaterally. Computed tomography angiography showed segmental and multifocal vasoconstriction of the cerebral arteries. After treatment, clinical and radiological findings resolved, suggesting the patient had reversible cerebral vasoconstriction syndrome with posterior reversible encephalopathy syndrome. However, he had residual agraphia of the left hand. Language testing revealed no difficulties in oral expression, auditory comprehension, understanding of written language, or writing with the right hand. I-123 iodoamphetamine single-photon emission computed tomography showed residual dysfunction in the left superior parietal lobule. There were no apparent signs of other disconnection syndromes or neuroimaging abnormalities in the corpus callosum. We diagnosed left-hand agraphia due to left parietal dysfunction. Our case suggests that left superior parietal dysfunction without callosal lesions is a possible cause of left-hand agraphia. Neural mechanisms for writing with the right or left hand may be separable at the cortical level.