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Diaphragmatic reconstruction is required for extensive diaphragmatic defects associated with tumor resection. Methods using artificial mesh and autologous tissues, such as pedicled flaps, have been reported predominantly for diaphragmatic reconstruction. We present the case of a 61-year-old woman who presented with a 14 × 13 × 12 cm tumor in the abdominal cavity of the upper left abdomen on computed tomography. The diaphragm defect measuring 12 × 7 cm that occurred during excision of the malignant tumor was reconstructed using the rectus abdominis muscle and fascial flap. The flap has vertical and horizontal vascular axes; therefore, blood flow is stable. It also has the advantage of increasing the range of motion and reducing twisting of the vascular pedicles. Fascial flap does not require processing such as thinning and can be used during suture fixation. This procedure, which has rarely been reported so far, has many advantages and may be a useful option for diaphragm reconstruction.

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.

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.

In the production of cell-based meat, it is desirable to reduce animal-derived materials as much as possible to meet the challenges of sustainability. Here, we demonstrate the “cell sheet-based meat”: scaffold-free cell-based meat using cell sheet technology and characterize its texture and nutrients. Bovine myoblast cell sheets were prepared using temperature-responsive culture dishes (TRCDs) and 10 stacked cell sheets to fabricate three-dimensional tissue of 1.3–2.7 mm thickness. Hardness was increased by incubation on the TRCD and was further increased by boiling as is characteristic of natural meat. The wet weight percentage of total protein in the cell sheet was about half that of beef. In this method, large-sized items of cell sheet-based meat were also created by simply scaling up the TRCD. This method promises an environment-friendly food product.

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.

This article highlights the association between physical activity (PA) and seasonal variations in metabolic and vascular function in adults. Increasing PA is an important method for preventing cardiovascular disease (CVD) and all-cause mortality by improving blood glucose, blood pressure, blood lipid profiles, body fat, insulin resistance, and vascular function, such as endothelial function. Conversely, various factors, such as seasonal climate conditions, may affect the amount of PA that individuals undertake. Changes in PA often induce seasonal variations in metabolic and vascular function; the deterioration of such functions in winter is the most prominent, and there is clear evidence of an increased risk of CVD in this season. Understanding the influence of PA on seasonal variations observed in metabolic and vascular function is necessary for the management of these physiological functions. In this article summary, few studies have proven that maintaining PA can suppress the variations, and it remains unclear what types, intensities, and durations of regular PA are effective for circumventing seasonal impact. In addition to further studies, there is a need to educate individuals about the strategies to manage PA and other aspects of their lifestyles throughout the year, particularly in winter.

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 (β=0.30, p

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.

The complex of lysozyme with an N-acetylglucosamine tetramer shows a relatively strong hydrogen-bond network around a catalytic residue via high-resolution X-ray structural analysis. This indicates a potentially different hydrolysis mechanism to that through a glycosyl intermediate, and this is expected to be proved using neutron experiments., Lysozyme hydrolyzes the glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine in peptidoglycans located in the bacterial cell wall. The mechanism of the hydrolysis reaction of lysozyme was first studied more than 50 years ago; however, it has not yet been fully elucidated and various mechanisms are still being investigated. One reaction system that has commonly been proposed is that the lysozyme intermediate undergoes covalent ligand binding during hydrolysis. However, these findings resulted from experiments performed under laboratory conditions using fluorine-based ligands, which facilitate the formation of covalent bonds between the ligands and the catalytic side chain of lysozyme. More recently, high-resolution X-ray structural analysis was used to study the complex of lysozyme with an N-acetylglucosamine tetramer. As a result, the carboxyl group of Asp52 was found to form a relatively strong hydrogen-bond network and had difficulty binding covalently to C1 of the carbohydrate ring. To confirm this hydrogen-bond network, neutron test measurements were successfully performed to a resolution of better than 1.9 Å.

Most of the radioactive cesium (134Cs and 137Cs), which originated from the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, has remained in the soil and on plants as water-insoluble microparticles (termed as CsMPs) and maintained relatively high radioactivity levels in the district. However, it has been reported that the radioactive Cs has been absorbed by plants. To interpret this phenomenon, the authors investigated CsMPs to determine if they become soluble during filtration and dialysis experiments. Moreover, other physical properties, such as mechanical properties and thermal stability, were observed during the course of the relevant experiments. These properties can be obtained by using carbonized charcoal litter with CsMPs.

Background: We aimed to evaluate the effect of moderate-intensity seated exercise on metabolic outcomes in hypertensive individuals with or without exercise habits. Methods: Forty-two hypertensive individuals volunteered for this study and were classified into 3 groups by their habits and place for moderate-intensity exercise prior to this study: NONE (

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.

Vascular structures are essential for the survival of thick artificial three-dimensional (3D) tissues. However, it is difficult to create high-cell-density artificial tissue with vascular structures of a few hundred micrometers in diameter. Bioprinting technology can create artificial 3D tissues with vascular structures of a few hundred micrometers in diameter, but the cell density of bio-printed artificial 3D tissues is low. On the other hand, cell sheet technology can create high-cell-density artificial 3D tissues by stacking, but it is not possible to set small vascular structures at any place. In this study, we successfully demonstrated high-cell-density artificial 3D tissues with vascular-like structures by stacking cell sheets combined with bioprinting technology.

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-β1-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.

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.

The development of microelectromechanical systems has resulted in the rapid development of polydimethylpolysiloxane (PDMS) microfluidic devices for drug screening models. Various cell functions, such as the response of endothelial cells to fluids, have been elucidated using microfluidic devices. Additionally, organ-on-a-chip systems that include organs that are important for biological circulation, such as the heart, liver, pancreas, kidneys, and brain, have been developed. These organs realize the biological circulation system in a manner that cannot be reproduced by artificial organs; however, the flow channels between the organs are often artificially created by PDMS. In this study, we developed a microfluidic device consisting only of cells, by combining cell sheet technology with microtitanium wires. Microwires were placed between stacked fibroblast cell sheets, and the cell sheets adhered to each other, after which the microwires were removed leaving a luminal structure with a size approximately equal to the arteriolar size. The lumen structure was constructed using wires with diameters of 50, 100, 150, and 200 μ m, which were approximations of the arteriole diameters. Furthermore, using a perfusion device, we successfully perfused the luminal structure created inside the cell sheets. The results revealed that a culture solution can be supplied to a cell sheet with a very high cell density. The biofabrication technology proposed in this study can contribute to the development of organ-on-a-chip systems.

Some patients with pollen-food allergy syndrome (PFAS) develop systemic symptoms along with oral allergy syndrome upon ingesting processed foods as well as raw fruits and vegetables. This study aimed to investigate the efficacy of subcutaneous immunotherapy with birch pollen extract for patients with PFAS associated with soybean allergy. Subcutaneous immunotherapy with birch pollen extract was introduced in 6 patients with PFAS caused by alder/birch pollen and soybean allergy. An oral food challenge for ingestible amount of soy milk was performed before and 1 year after initiating subcutaneous immunotherapy with birch pollen extract. Before the treatment, the median intake of soy milk was 1.5 mL (interquartile range [IQR], 1-2 mL). One year after the treatment initiation, the median intake of soy milk increased significantly to 150 mL (IQR, 20-200 mL). Systemic reactions occurred in 4 of 6 patients in the rapid escalation phase of the treatment. The results thus suggest that subcutaneous immunotherapy with birch pollen extract could be beneficial for patients with PFAS associated with soybean allergy despite concerns regarding systemic reactions.

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.

Alveolar epithelial injury induced by reactive oxygen species (ROS) and abnormal collagen production by activated fibroblasts (myofibroblasts) is involved in the onset and exacerbation of idiopathic pulmonary fibrosis (IPF). Compared with alveolar epithelial cells, lung fibroblasts, especially myofibroblasts, exhibit an apoptosis-resistance phenotype (apoptosis paradox) that appears to be involved in IPF pathogenesis. Thus, we screened for chemicals eliciting preferential cytotoxicity of LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human lung alveolar epithelial cell line) from medicines already in clinical use. We identified idebenone, a synthetic analogue of coenzyme Q10 (CoQ10, an antioxidant) that has been used clinically as a brain metabolic stimulant. Idebenone induced cell growth inhibition and cell death in LL29 cells at a lower concentration than in A549 cells, a feature that was not observed for other antioxidant molecules (such as CoQ10) and two IPF drugs (pirfenidone and nintedanib). Administration of idebenone prevented bleomycin-induced pulmonary fibrosis and increased pulmonary ROS levels. Importantly, idebenone also improved pulmonary fibrosis and lung function when administered after the development of fibrosis, whereas administration of CoQ10 similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ10, suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ10, suppressed TGF-β–induced collagen production. These results suggest that in addition to antioxidant activity, idebenone exerts inhibitory activity on the function of lung fibroblasts, with the former activity being preventative and the latter therapeutic for bleomycin-induced fibrosis. Thus, we propose that idebenone may be more therapeutically beneficial for IPF patients than current treatments.

Conductive ceramic films, such as indium tin oxide (ITO) and zinc oxide (ZnO) thin films, are expected to be used as core semiconducting materials for applications for the Internet of Things (IoT). In this study, we focused on a nonequilibrium excitation reaction field as a bottom-up architecture, and we successfully found the basis of a technology for fabricating the above films using a plasma atmosphere and an electron beam that uniformly emits electrons within a plane as a nonequilibrium reaction field. In particular, the ZnO thin film obtained in this study exhibited good electrical properties, such as a high Hall mobility of 128.3 cm2/V, even though it was formed on a polyethylene terephthalate (PET) film substrate at room temperature. This achievement may contribute to clarifying the mechanism behind the fabrication of highly functional oxide thin films by a two-dimensional simple process without thermal treatment of the substrate during the film formation. Moreover, this technique will also enable us to provide elements for next-generation nanodevices in IoT by controlling the surface and interface of nanostructures as well as highly functional properties using complexes of metals, ceramics, and semiconductors.

We theoretically study low-temperature properties of the antiferromagnetic Heisenberg model with half-integer spin $S$ on the Kagome lattice with large trimerization. We have derived a low-energy effective model for general $S$ in terms of spin and nematicity operators in triangular units, and studied their low-temperature correlations for S=3/2 by classical Monte Carlo simulations. The previous study for the S=1/2 case [M. Ferrero et al., Phys. Rev. B 68, 214431 (2003)] reported a spin liquid state at low temperatures driven by a glassy behavior of isolated dimers and trimers of nematicities. The results for S=3/2 show that nematicity dimers and trimers are connected by weak links to form a defective planar network. At very low temperatures, nematicities show glassy slow dynamics, and cluster spins continue to fluctuate in a nonperiodically frozen background of nematicities. The characteristic time of glassy dynamics scales with temperature following a power law., Comment: 5 pages, 6 figures

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.

Introduction Endothelium‐dependent flow‐mediated dilation (FMD) of the brachial artery often changes seasonally. We aimed to examine the association between the seasonal variation on FMD and regular exercise in adults with type 2 diabetes (T2D) and nondiabetic adults with hypertension and/or dyslipidaemia (non‐T2D). Methods This retrospective study included 14 T2D and 17 non‐T2D adults, who started to perform moderate‐intensity aerobic exercise for 30‐40 min/d at a hospital gym in 2006‐2010 and maintained exercise performance at least 2 d/wk until the end of the observation period. We observed and analysed the data for 5 years (from March 2011 to February 2016). FMD, cardio‐ankle vascular index (CAVI) and metabolic outcomes were compared among seasons in the T2D and non‐T2D groups. Results The FMD values were lower in winter than in other seasons in both groups (all P, Flow‐mediated vasodilation (FMD) seasonally varies in adults with type 2 diabetes and nondiabetic adults with hypertension and/or dyslipidaemia despite performing long‐term exercises. Annual range of FMD may increase with the presence of type 2 diabetes.

ObjectivesThis study aimed to examine whether maintaining supervised gym- and home-based exercises for an extended time of period could decrease seasonal variations of metabolic outcomes in overweight and obese Japanese adults.MethodsThis retrospective study recruited 54 overweight and obese outpatients who started exercising in 2006–2010 and analysed their metabolic outcomes for 5 years from March 2011 to February 2016. In this group, 26 participants performed moderate-intensity aerobic exercise (MIAE) for 30–40 min/day for at least 2 days/week, supervised by physical therapists at a hospital gym (GYM) during the observation period. Conversely, 28 participants were asked to perform MIAE by themselves at or around their homes (HOME) for the same duration.ResultsThe body mass index (BMI), waist circumference and homoeostasis model assessment of insulin resistance (HOMA-IR) values in winter were higher than those in other seasons in the HOME group but not in the GYM group. The annual ranges of BMI, waist circumference, fasting plasma glucose and HOMA-IR in the GYM group were smaller than those in the HOME group.ConclusionMaintaining supervised gym-based exercise, as opposed to home-based exercise, may decrease seasonal variations of some metabolic outcomes in overweight and obese Japanese adults.

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 (β-alanyl histidine) as a possible therapeutic agent for vascular dementia.

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13340-020-00463-5) contains supplementary material, which is available to authorized users.

Conformational changes in amyloidogenic proteins, such as β-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 β-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.

The adenosine A2B receptor is a critical protein in intestinal water secretion. In the present study, we screened compound libraries to identify inhibitors of the A2B receptor and evaluated their effect on adenosine-induced intestinal fluid secretion. The screening identified the dihydropyridine calcium antagonists nifedipine and nisoldipine. Their respective affinities for the A2B receptor (Ki value) were 886 and 1,399 nM. Nifedipine and nisoldipine, but not amlodipine or nitrendipine, inhibited both calcium mobilization and adenosine-induced cAMP accumulation in cell lines. Moreover, adenosine injection into the lumen significantly increased fluid volume in the colonic loop of wild-type mice but not A2B receptor-deficient mice. PSB-1115, a selective A2B receptor antagonist, and nifedipine prevented elevated adenosine-stimulated fluid secretion in mice. Our results may provide useful insights into the structure–activity relationship of dihydropyridines for A2B receptor. As colonic fluid secretion by adenosine seems to rely predominantly on the A2B receptor, nifedipine could be a therapeutic candidate for diarrhoea-related diseases.

Background Recent studies have suggested that chronic kidney disease is associated with cardiovascular disease, dementia, and frailty, all of which cause disability and early death. We investigated whether increased activity of urinary N-acetyl-β-glucosaminidase (NAG), a marker of kidney injury, is associated with risk of disability or all-cause mortality in a general population. Methods Follow-up data from the Hidaka Cohort Study, a population-based cohort study of members of a Japanese rural community, were obtained via questionnaires completed by participants or their relatives. Multivariable analyses were used to investigate relations between urinary NAG activity–urinary creatinine concentration ratio and risk of disability or all-cause mortality. Results A total of 1182 participants were followed up for a median of 12.4 years. The endpoints were receipt of support under the public long-term care insurance program, and all-cause mortality. A total of 122 participants (10.3%) were reported to be receiving long-term care and 230 (19.5%) had died. After adjustment for cardiovascular risk factors along with physical activity, and using the quartile 1 results as a reference, the odds ratio (OR) for disability was 2.12 [95% confidence interval (95% confidence interval [CI]), 1.04–4.33; p = 0.038) and the hazard ratio (HR) for all-cause mortality was 1.65 (95% CI, 1.05–2.62; p = 0.031) in participants with urinary NAG/creatinine ratio in quartile 4. Similar results were obtained in participants without proteinuria: OR for disability, 2.46 (95% CI, 1.18–5.16; p = 0.017); and HR for all-cause mortality, 1.62 (95% CI, 1.00–2.63; p = 0.049). Conclusions Increased urinary NAG/creatinine ratio was associated with risk of disability or all-cause mortality in a general population.

In this article, the status of the STARGazer data-processing software and its data-processing algorithms are described in detail. The STARGazer data-processing software is used for neutron time-of-flight single-crystal diffraction data collected using the IBARAKI Biological Crystal Diffractometer., The STARGazer data-processing software is used for neutron time-of-flight (TOF) single-crystal diffraction data collected using the IBARAKI Biological Crystal Diffractometer (iBIX) at the Japan Proton Accelerator Research Complex (J-PARC). This software creates hkl intensity data from three-dimensional (x, y, TOF) diffraction data. STARGazer is composed of a data-processing component and a data-visualization component. The former is used to calculate the hkl intensity data. The latter displays the three-dimensional diffraction data with searched or predicted peak positions and is used to determine and confirm integration regions. STARGazer has been developed to make it easier to use and to obtain more accurate intensity data. For example, a profile-fitting method for peak integration was developed and the data statistics were improved. STARGazer and its manual, containing installation and data-processing components, have been prepared and provided to iBIX users. This article describes the status of the STARGazer data-processing software and its data-processing algorithms.

To improve the sensitivity of hydrogen detection using neutrons, high-pressure cooling of a relatively large protein single crystal and proton polarization of a protein polycrystalline state have been demonstrated as preliminary experiments., To improve the sensitivity of hydrogen detection using neutrons, a proton-polarization technique together with a high-pressure cooling method is necessary. The highest pressure (200 MPa) used in the experiment described here enabled relatively large protein crystals to be cooled without any cryoprotectants while retaining the protein structure, and it was confirmed that high-pressure-cooled crystals diffracted to nearly the same resolution as flash-cooled small crystals soaked with cryoprotectants. Dynamic nuclear polarization was used as a proton-polarization technique for protein crystals, and ∼300 mg polycrystalline protein doped with TEMPOL gave a maximum proton polarization of 22.3% at a temperature of 0.5 K in a 2.5 T magnetic field.