Ergothioneine Prevents Neuronal Cell Death Caused by the Neurotoxin 6-Hydroxydopamine.

Neuronal cell death is a key mechanism involved in the development and exacerbation of Parkinson's disease (PD). The excessive production of reactive oxygen species (ROS) is a major cause leading to neuronal death; therefore, compounds that prevent oxidative stress-dependent neuronal death may be promising as a preventive method for PD. Ergothioneine is a natural amino acid with antioxidant properties, and its protective functions in the body are attracting attention. However, there has been no investigation into the protective functions of ergothioneine using in vivo and in vitro PD models. Thus, in this study, we analyzed the efficacy of ergothioneine against 6-hydroxydopamine (6-OHDA)-dependent neuronal cell death using immortalized hypothalamic neurons (GT1-7 cells). First, we found that ergothioneine prevents 6-OHDA-dependent neuronal cell death by suppressing ROS overproduction in GT1-7 cells. The cytoprotective effect of ergothioneine was partially abolished by verapamil, an inhibitor of OCTN1, which is involved in ergothioneine uptake. Furthermore, ergothioneine-rich Rice-koji (Ergo-koji) showed cytoprotective and antioxidant effects similar to those of ergothioneine. Taken together, these results suggest that ergothioneine or foods containing ergothioneine may be an effective method for preventing the development and progression of PD.

Dietary Trace Elements and the Pathogenesis of Neurodegenerative Diseases.

Trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are absorbed from food via the gastrointestinal tract, transported into the brain, and play central roles in normal brain functions. An excess of these trace elements often produces reactive oxygen species and damages the brain. Moreover, increasing evidence suggests that the dyshomeostasis of these metals is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, prion diseases, and Lewy body diseases. The disease-related amyloidogenic proteins can regulate metal homeostasis at the synapses, and thus loss of the protective functions of these amyloidogenic proteins causes neurodegeneration. Meanwhile, metal-induced conformational changes of the amyloidogenic proteins contribute to enhancing their neurotoxicity. Moreover, excess Zn and Cu play central roles in the pathogenesis of vascular-type senile dementia. Here, we present an overview of the intake, absorption, and transport of four essential elements (Fe, Zn, Cu, Mn) and one non-essential element (aluminum: Al) in food and their connections with the pathogenesis of neurodegenerative diseases based on metal-protein, and metal-metal cross-talk.

Effectiveness of Albumin-Fused Thioredoxin against 6-Hydroxydopamine-Induced Neurotoxicity In Vitro.

Parkinson's disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder are lacking. Thioredoxin is the major protein disulfide reductase in vivo. We previously synthesized an albumin-thioredoxin fusion protein (Alb-Trx), which has a longer plasma half-life than thioredoxin, and reported its effectiveness in the treatment of respiratory and renal diseases. Moreover, we reported that the fusion protein inhibits trace metal-dependent cell death in cerebrovascular dementia. Here, we investigated the effectiveness of Alb-Trx against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Alb-Trx significantly inhibited 6-OHDA-induced neuronal cell death and the integrated stress response. Alb-Trx also markedly inhibited 6-OHDA-induced reactive oxygen species (ROS) production, at a concentration similar to that inhibiting cell death. Exposure to 6-OHDA perturbed the mitogen-activated protein kinase pathway, with increased phosphorylated Jun N-terminal kinase and decreased phosphorylated extracellular signal-regulated kinase levels. Alb-Trx pretreatment ameliorated these changes. Furthermore, Alb-Trx suppressed 6-OHDA-induced neuroinflammatory responses by inhibiting NF-κB activation. These findings suggest that Alb-Trx reduces neuronal cell death and neuroinflammatory responses by ameliorating ROS-mediated disruptions in intracellular signaling pathways. Thus, Alb-Trx may have potential as a novel therapeutic agent for PD.

Attenuation of LPS-Induced Lung Injury by Benziodarone via Reactive Oxygen Species Reduction.

As overproduction of reactive oxygen species (ROS) causes various diseases, antioxidants that scavenge ROS, or inhibitors that suppress excessive ROS generation, can be used as therapeutic agents. From a library of approved drugs, we screened compounds that reduced superoxide anions produced by pyocyanin-stimulated leukemia cells and identified benzbromarone. Further investigation of several of its analogues showed that benziodarone possessed the highest activity in reducing superoxide anions without causing cytotoxicity. In contrast, in a cell-free assay, benziodarone induced only a minimal decrease in superoxide anion levels generated by xanthine oxidase. These results suggest that benziodarone is an inhibitor of NADPH oxidases in the plasma membrane but is not a superoxide anion scavenger. We investigated the preventive effect of benziodarone on lipopolysaccharide (LPS)-induced murine lung injury as a model of acute respiratory distress syndrome (ARDS). Intratracheal administration of benziodarone attenuated tissue damage and inflammation via its ROS-reducing activity. These results indicate the potential application of benziodarone as a therapeutic agent against diseases caused by ROS overproduction.

Preventive Effect of Epigallocatechin Gallate, the Main Component of Green Tea, on Acute Lung Injury Caused by Air Pollutants.

Reducing the health hazards caused by air pollution is a global challenge and is included in the Sustainable Development Goals. Air pollutants, such as PM2.5, induce respiratory and cardiovascular disorders by causing various inflammatory responses via oxidative stress. Catechins and polyphenols, which are components of green tea, have various protective effects, owing to their antioxidant ability. The main catechin in green tea, epigallocatechin gallate (EGCG), is potentially effective against respiratory diseases, such as idiopathic pulmonary fibrosis and asthma, but its effectiveness against air-pollution-dependent lung injury has not yet been investigated. In this study, we examined the effect of EGCG on urban aerosol-induced acute lung injury in mice. Urban aerosol treatment caused increases in inflammatory cell counts, protein levels, and inflammatory cytokine expression in the lungs of ICR mice, but pretreatment with EGCG markedly suppressed these responses. Analyses of oxidative stress revealed that urban aerosol exposure enhanced reactive oxygen species (ROS) production and the formation of ROS-activated neutrophil extracellular traps (NETs) in the lungs of mice. However, ROS production and NETs formation were markedly suppressed by pretreating the mice with EGCG. Gallocatechin gallate (GCG), a heat-epimerized form of EGCG, also markedly suppressed urban aerosol-dependent inflammatory responses and ROS production in vivo and in vitro. These findings suggest that EGCG and GCG prevent acute lung injury caused by urban aerosols through their inhibitory effects on ROS production. Thus, we believe that foods and medications containing EGCG or GCG may be candidates to prevent the onset and progression of acute lung injury caused by air pollutants.

Crosstalk of copper and zinc in the pathogenesis of vascular dementia.

Copper and zinc are essential for normal brain functions. Both are localized in presynaptic vesicles and are secreted into synaptic clefts during neuronal excitation. Despite their significance, excesses of copper and zinc are neurotoxic. In particular, excess zinc after transient global ischemia plays a central role in the ischemia-induced neurodegeneration and pathogenesis of vascular type senile dementia. We previously found that sub-lethal concentrations of copper remarkably exacerbated zinc-induced neurotoxicity, and we investigated the molecular pathways of copper-enhanced zinc-induced neurotoxicity. The endoplasmic reticulum stress pathway, the stress-activated protein kinases/c-|Jun amino-terminal kinases pathway, and mitochondrial energy production failure were revealed to be involved in the neurodegenerative processes. Regarding the upstream factors of these pathways, we focused on copper-derived reactive oxygen species and the disruption of calcium homeostasis. Because excess copper and zinc may be present in the synaptic clefts during ischemia, it is possible that secreted copper and copper-induced reactive oxygen species may enhance zinc neurotoxicity and eventually contribute to the pathogenesis of vascular type senile dementia.

Exacerbation of Elastase-Induced Emphysema via Increased Oxidative Stress in Metallothionein-Knockout Mice.

Although the pathogenesis of chronic obstructive pulmonary disease (COPD) is not yet fully understood, recent studies suggest that the disruption of the intracellular balance of oxidative (such as reactive oxygen species (ROS)) and antioxidant molecules plays an important role in COPD development and progression. Metallothionein is an endogenous metal-binding protein with reported ROS scavenging activity. Although there have been many publications on the protective effects of metallothionein in the kidney and liver, its role in COPD models such as elastase- or cigarette smoke (CS)-induced lung injury is unknown. Thus, in the present study, we analyzed the elastase-induced lung injury model using metallothionein-knockout (MT-KO; MT-1 and -2 gene deletion) mice. The expression of MT-1 and MT-2 in the lungs of MT-KO mice was markedly lower compared with that in the lungs of wildtype (WT) mice. Porcine pancreatic elastase (PPE)-induced lung injury (alveolar enlargement and respiratory impairment) was significantly exacerbated in MT-KO mice compared with WT mice. Additionally, PPE-induced increases in the number of inflammatory cells, inflammatory cytokines, and cell death in lung tissue were significantly more pronounced in MT-KO mice compared with WT mice. Finally, using an in vivo imaging system, we also found that PPE-induced ROS production in the lungs was enhanced in MT-KO mice compared with WT mice. These results suggest that metallothionein may act as an inhibitor against elastase-induced lung injury by suppressing ROS production. These results suggest that metallothionein protein, or compounds that can induce metallothionein, could be useful in the treatment of COPD.

Therapeutic effects of eperisone on pulmonary fibrosis via preferential suppression of fibroblast activity.

Although the exact pathogenesis of idiopathic pulmonary fibrosis (IPF) is still unknown, the transdifferentiation of fibroblasts into myofibroblasts and the production of extracellular matrix components such as collagen, triggered by alveolar epithelial cell injury, are important mechanisms of IPF development. In the lungs of IPF patients, apoptosis is less likely to be induced in fibroblasts than in alveolar epithelial cells, and this process is involved in the pathogenesis of IPF. We used a library containing approved drugs to screen for drugs that preferentially reduce cell viability in LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human alveolar epithelial cell line). After screening, we selected eperisone, a central muscle relaxant used in clinical practice. Eperisone showed little toxicity in A549 cells and preferentially reduced the percentage of viable LL29 cells, while pirfenidone and nintedanib did not have this effect. Eperisone also significantly inhibited transforming growth factor-ß1-dependent transdifferentiation of LL29 cells into myofibroblasts. In an in vivo study using ICR mice, eperisone inhibited bleomycin (BLM)-induced pulmonary fibrosis, respiratory dysfunction, and fibroblast activation. In contrast, pirfenidone and nintedanib were less effective than eperisone in inhibiting BLM-induced pulmonary fibrosis under this experimental condition. Finally, we showed that eperisone did not induce adverse effects in the liver and gastrointestinal tract in the BLM-induced pulmonary fibrosis model. Considering these results, we propose that eperisone may be safer and more therapeutically beneficial for IPF patients than current therapies.

Novel pharmacological effects of lecithinized superoxide dismutase on ischemia/reperfusion injury in the kidneys of mice.

Renal ischemia/reperfusion (I/R) injury is a major clinical problem because it can cause acute kidney injury (AKI) or lead to the transition from AKI to chronic kidney disease (CKD). Oxidative stress, which involves the production of reactive oxygen species (ROS), plays an important role in the development and exacerbation of I/R-induced kidney injury. However, we have previously reported that lecithinized superoxide dismutase (PC-SOD), a SOD derivative with high tissue affinity and high stability in plasma, has beneficial effects in various disease models because of its inhibitory effect on ROS production. Therefore, we aimed to determine the effects of intravenous PC-SOD administration in a mouse model of renal injury induced by I/R. PC-SOD markedly ameliorated the I/R-induced increases in markers of renal damage (urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and interleukin-6) and tubular necrosis 48 h after the intervention. We also found that PC-SOD significantly ameliorated the I/R-induced increase in ROS production, using an ex vivo imaging system. Furthermore, PC-SOD inhibited the increases in expression of markers of fibrosis (α-smooth muscle actin and collagen 1A1) 96 h after, and renal fibrosis 25 days after I/R was induced. Finally, we found that PC-SOD ameliorated the I/R-induced AKI in mice with high-fat diet-induced prediabetes. These results suggest that PC-SOD inhibits AKI and the transition from AKI to CKD through the inhibition of ROS production. Therefore, we believe that PC-SOD may represent an effective therapeutic agent for I/R-induced renal injury.

Copper as a Collaborative Partner of Zinc-Induced Neurotoxicity in the Pathogenesis of Vascular Dementia.

Copper is an essential trace element and possesses critical roles in various brain functions. A considerable amount of copper accumulates in the synapse and is secreted in neuronal firings in a manner similar to zinc. Synaptic copper and zinc modulate neuronal transmission and contribute to information processing. It has been established that excess zinc secreted during transient global ischemia plays central roles in ischemia-induced neuronal death and the pathogenesis of vascular dementia. We found that a low concentration of copper exacerbates zinc-induced neurotoxicity, and we have demonstrated the involvement of the endoplasmic reticulum (ER) stress pathway, the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) signaling pathway, and copper-induced reactive oxygen species (ROS) production. On the basis of our results and other studies, we discuss the collaborative roles of copper in zinc-induced neurotoxicity in the synapse and the contribution of copper to the pathogenesis of vascular dementia.

High glucose promotes mineralization via bone morphogenetic protein 4-Smad signals in early stage of osteoblast differentiation.

Diabetes mellitus is associated with bone fragility. Although osteoblast maturation is disturbed in patients with diabetes mellitus, the involvement of high glucose (HG) in different stages of osteoblast maturation is unclear. We used MC3T3-E1 cells, a murine osteoblastic cell line. The cells were incubated in high glucose medium (16.5 and 27.5 mM) with three different time courses: throughout 21 days, only first 7 days (early stage) and only last 7 days (late stage). Mineralization assay showed that HG throughout 21 days increased mineralization compared with control (5.5 mM). In the time course experiment, HG increased mRNA expression of Alp, osteocalcin (Ocn), runt-related transcription factor 2 and osterix on days 3 and 5. By contrast, long-term treatment with HG (14 and 21 days) decreased expression of these osteoblastic markers. HG only during early stage enhanced mineralization, while HG only during late stage had no effects. HG increased the expression of bone morphogenetic protein (BMP) 4 and enhanced phosphorylation of Smad1/5/8. Treatment with a BMP receptor antagonist LDN193189 prevented the HG-induced mineralization during early stage of osteoblast differentiation, indicating that HG in the early stage promotes mineralization by BMP4. In conclusion, the study demonstrates that continuous HG treatment might enhance early osteoblast differentiation but disturbs osteoblast maturation, and that BMP-4-Smad signal might be involved in the HG-induced differentiation and mineralization of osteoblasts.

Neurometals in the Pathogenesis of Prion Diseases.

Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrPC) into abnormal pathogenic prion protein (PrPSc) is critical for its infection and pathogenesis. PrPC possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrPC plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrPC. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrPC and the neurotoxicity of PrPSc.

Higher Serum Uric Acid is a Risk Factor of Reduced Muscle Mass in Men with Type 2 Diabetes Mellitus.

OBJECTIVE: Sarcopenia has been recognized as a diabetic complication, and hyperuricemia is often accompanied by type 2 diabetes mellitus (T2DM). However, it is unknown whether serum uric acid (UA) levels are associated with reduced muscle mass in T2DM. METHODS: We conducted a cross-sectional study to investigate the association of serum UA with muscle mass in 401 subjects with T2DM (209 men and 192 postmenopausal women). The relative skeletal muscle mass index (RSMI) was evaluated using whole-body dual-energy x-ray absorptiometry. RESULTS: Multiple regression analyses adjusted for body weight, age, serum creatinine, hemoglobin A1c (HbA1c), and duration of T2DM showed that serum UA was negatively associated with RSMI in all subjects and men with T2DM (ß=-0.13, p=0.001 and ß=-0.17, p=0.003, respectively). Moreover, logistic regression analyses adjusted for these confounding factors showed that a higher serum UA level was significantly associated with low RSMI in men with T2DM [odds ratio (OR)=1.94, 95% confidence interval (CI)=1.10-3.45 per SD increase, p=0.023]. In addition, higher serum UA levels were significantly associated with low RSMI after additional adjustment for age, duration of T2DM, HbA1c level, serum creatinine level, and sex in all subjects with T2DM [OR=1.80, 95% CI=1.20-2.72 per SD increase, p=0.005]. CONCLUSIONS: The present study showed for the first time that higher serum UA is an independent risk factor of reduced muscle mass in men with T2DM.

Which Is a Better Skeletal Muscle Mass Index for the Evaluation of Physical Abilities: The Present Height or Maximum Height?

Objective Sarcopenia and osteoporosis often coexist in older adults. Sarcopenia is diagnosed using the skeletal muscle mass index (SMI), which is calculated as the appendicular skeletal muscle mass (ASM)/(present height)2, although patients with osteoporosis frequently have a loss of body height. We therefore investigated whether the present height or maximum height is more useful for calculating the SMI in the evaluation of physical abilities. Methods We conducted a cross-sectional study to investigate the association of the SMI with physical abilities, such as the grip strength and gait speed, in 587 postmenopausal women. The SMI was evaluated using whole-body dual-energy X-ray absorptiometry (DXA). The SMI [(ASM)/(present height)2], modified SMI (mSMI) [(ASM)/(maximum height)2], and SMI difference (ΔSMI) (mSMI-SMI) were calculated. Results Age and body mass index (BMI)-adjusted regression analyses showed that the SMI (ß=0.30, p<0.001 and ß=0.14, p=0.034) and mSMI (ß=0.40, p<0.001 and ß=0.29, p<0.001) were positively associated while the ΔSMI was negatively associated with the grip strength and gait speed (ß=-0.15, p<0.001 and ß=-0.24, p<0.001, respectively). Furthermore, the age, BMI, and presence of osteoporotic fractures-adjusted logistic regression analyses showed that a low mSMI (<5.4 kg/m2) was significantly associated with a low grip strength (<18 kg) and slow gait speed (1.0 m/s) [odds ratio (OR) =2.45, 95% confidence interval (CI) =1.52-3.95 per SD increase, p<0.001; and OR=1.73, 95% CI=1.01-2.96, p=0.042, respectively], although a low SMI showed no such relationship (p=0.052 and p=0.813, respectively). Conclusion The mSMI using the maximum height is more useful for evaluating physical abilities than conventional SMI estimation in postmenopausal women.

Thioredoxin-albumin fusion protein prevents urban aerosol-induced lung injury via suppressing oxidative stress-related neutrophil extracellular trap formation.

The number of deaths from air pollution worldwide is estimated at 8.8 million per year, more than the number of deaths from smoking. Air pollutants, such as PM2.5, are known to induce respiratory and cardiovascular diseases by inducing oxidative stress. Thioredoxin (Trx) is a 12-kDa endogenous protein that exerts antioxidant activity by promoting dithiol disulfide exchange reactions. We previously synthesized human serum albumin-fused thioredoxin (HSA-Trx), which has a longer half-life in plasma compared with Trx, and demonstrated its efficacy against various diseases including respiratory diseases. Here, we examined the effect of HSA-Trx on urban aerosol-induced lung injury in mice. Urban aerosols induced lung injury and inflammatory responses in ICR mice, but intravenous administration of HSA-Trx markedly inhibited these responses. We next analyzed reactive oxygen species (ROS) production in murine lungs using an in vivo imaging system. The results show that intratracheal administration of urban aerosols induced ROS production that was inhibited by intravenously administered HSA-Trx. Finally, we found that HSA-Trx inhibited the urban aerosol-induced increase in levels of neutrophilic extracellular trap (NET) indicators (i.e., double-stranded DNA, citrullinated histone H3, and neutrophil elastase) in bronchoalveolar lavage fluid (BALF). Together, these findings suggest that HSA-Trx prevents urban aerosol-induced acute lung injury by suppressing ROS production and neutrophilic inflammation. Thus, HSA-Trx may be a potential candidate drug for preventing the onset or exacerbation of lung injury caused by air pollutants.

Carnosine suppresses neuronal cell death and inflammation induced by 6-hydroxydopamine in an in vitro model of Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disease for which prevention and effective treatments are lacking. The pathogenesis of Parkinson's disease is not clearly understood. It is thought to be caused by oxidative stress-dependent loss of dopamine neurons in the substantia nigra and the promotion of inflammatory responses by microglia at the lesion site. In addition, cell loss occurs in the hypothalamus of Parkinson's disease patients. Carnosine is an endogenous dipeptide that can exert many beneficial effects, including an antioxidant action, metal ion chelation, proton buffering capacity, and inhibition of protein carbonylation and glycolysis. Previously, we found that carnosine inhibits trace metal-induced death of immortalized hypothalamic neuronal GT1-7 cells. In this study, we analyzed the efficacy of carnosine on 6-hydroxydopamine (6-OHDA)-dependent GT1-7 cell death and inflammatory responses. We found that carnosine significantly prevented 6-OHDA-dependent GT1-7 cell death in a dose-dependent manner. Moreover, carnosine significantly suppressed the expression of 6-OHDA-induced integrated stress response (ISR)-related factors and pro-inflammatory cytokines. Carnosine also significantly inhibited 6-OHDA-dependent reactive oxygen species (ROS) production and c-Jun amino-terminal kinase (JNK) pathway activation in GT1-7 cells. These results indicate that carnosine inhibits hypothalamic neuronal cell death and inflammatory responses by inhibiting the ROS-JNK pathway. We therefore suggest that carnosine may be effective in preventing the onset or the exacerbation of Parkinson's disease.

Seleno-l-methionine suppresses copper-enhanced zinc-induced neuronal cell death via induction of glutathione peroxidase.

Excessive zinc ion (Zn2+) release is induced in pathological situations and causes neuronal cell death. Previously, we have reported that copper ions (Cu2+) markedly exacerbated Zn2+-induced neuronal cell death by potentiating oxidative stress, the endoplasmic reticulum (ER) stress response, and the activation of the c-Jun amino-terminal kinase (JNK) signaling pathway. In contrast, selenium (Se), an essential trace element, and amino acids containing selenium (such as seleno-l-methionine) have been reported to inhibit stress-induced neuronal cell death and oxidative stress. Thus, we investigated the effect of seleno-l-methionine on Cu2+/Zn2+-induced neuronal cell death in GT1-7 cells. Seleno-l-methionine treatment clearly restored the Cu2+/Zn2+-induced decrease in the viable cell number and attenuated the Cu2+/Zn2+-induced cytotoxicity. Accordingly, the levels of ER stress-related factors (especially, CHOP and GADD34) and of phosphorylated JNK increased upon CuCl2 and ZnCl2 co-treatment, whereas pre-treatment with seleno-l-methionine significantly suppressed these upregulations. Analysis of reactive oxygen species (ROS) as upstream factors of these pathways revealed that Cu2+/Zn2+-induced ROS production was clearly suppressed by seleno-l-methionine treatment. Finally, we found that seleno-l-methionine induced the antioxidative protein, glutathione peroxidase. Taken together, our findings suggest that seleno-l-methionine suppresses Cu2+/Zn2+-induced neuronal cell death and oxidative stress via induction of glutathione peroxidase. Thus, we think that seleno-l-methionine may help prevent refractory neurological diseases.

Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia.

Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (ß-alanyl histidine) as a possible therapeutic agent for vascular dementia.

Amyloids: Regulators of Metal Homeostasis in the Synapse.

Conformational changes in amyloidogenic proteins, such as ß-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer's disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with ß-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.