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.

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.

Descattering for transmissive inspection in production line using slanted linear image sensors.

We propose a descattering method that can be easily applied to food production lines. The system consists of several sets of linear image sensors and linear light sources slanted at different angles. The images captured by these sensors are partially clear along the direction perpendicular to the sensors. We computationally integrate these images on the frequency domain into a single clear image. The effectiveness of the proposed method is assessed by simulation and real-world experiments. The results show that our method recovers clear images. We demonstrate the applicability of the proposed method to a real production line by a prototype system.

Genomic landscape of circulating tumour DNA in metastatic extramammary Paget's disease.

Although cancer personalized profiling by deep sequencing (CAPP-Seq) of cell-free DNA (cfDNA) has gained attention, the clinical utility of circulating tumour DNA (ctDNA) in extramammary Paget's disease (EMPD) has not been investigated. In this study, genomic alterations in the cfDNA and tumour tissue DNA were investigated in seven patients with metastatic EMPD. CAPP-Seq revealed mutations in 18 genes, 11 of which have not yet been reported in EMPD. The variant allele frequency of some of the mutated genes reflected the disease course in patients with EMPD. In one patient, the mutation was detected even though imaging findings revealed no metastasis. In another patient with triple EMPD (genital area and both axilla), cfDNA sequencing detected the mutation in a rib metastatic lesion, which was also detected in both axilla lesions but not the genital region. Investigations of the ctDNA may be useful towards the elucidation of clonal evolution in EMPD.

Repeated Cardioembolic Stroke after COVID-19 mRNA Vaccination: A Case Report.

OBJECTIVE: There have been no reports suggesting a relationship between the COVID-19 mRNA vaccines that encodes the spike glycoprotein of SARS-CoV-2 and cerebrovascular disease. A case of repeated cardioembolic stroke after vaccination with the BNT162b2 (Pfizer) COVID-19 mRNA vaccine is presented. METHODS: Imaging and laboratory findings, treatment decisions, and the outcome of this case are presented. RESULTS: An 83-year-old Japanese woman developed right hemiplegia and motor aphasia three days after receiving her first dose of the BNT162b2 (Pfizer) COVID-19 mRNA vaccine. She had been taking rivaroxaban for persistent atrial fibrillation for 10 years, but had no symptomatic ischemic strokes. On magnetic resonance imaging (MRI) the left middle cerebral artery (MCA) was occluded. Intravenous recombinant tissue-plasminogen activator (rt-PA) therapy and mechanical thrombectomy were performed, and she recovered almost fully. However, three days after the second dose, she developed left hemiplegia and left hemispatial neglect. MRI showed occlusion of the right MCA. Only mechanical thrombectomy was performed again, but it could not be resumed due to the hard thrombus. DISCUSSION: In this case, it is difficult to exclude a causal relationship between the COVID-19 mRNA vaccine and ischemic stroke. This association needs to be carefully monitored.

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.

Time-of-flight imaging in fog using multiple time-gated exposures.

We propose a time-of-flight measurement algorithm for depth and intensity that is robust to fog. The key idea of the algorithm is to compensate for the scattering effects of fog by using multiple time-gating and assigning one time-gated exposure for scattering property estimation. Once the property is estimated, the depth and intensity can be reconstructed from the rest of the exposures via a physics-based model. Several experiments with artificial fog show that our method can measure depth and intensity irrespective of the traits of the fog. We also confirm the effectiveness of our method in real fog through an outdoor experiment.

Super-resolution for a dispersive spectrometer using a tilted area sensor and spectrally varying blur kernel interpolation.

The grating, lens, and linear sensor determine a spectrometer's wavelength resolution and measurement range. While conventional methods have tried to improve the optical design to obtain a better resolution, they have a limitation caused by the physical property. To improve the resolution, we introduce a super-resolution method from the computer vision field. We propose tilting an area sensor to realize accurate subpixel shifting and recover a high-resolution spectrum using interpolated spectrally varying kernels. We experimentally validate that the proposed method achieved a high spectral resolution of 0.141nm in 400-800nm by just tilting the sensor in the spectrometer.

FAM210A is a novel determinant of bone and muscle structure and strength.

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a-/- ), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus-/- ). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a-/- mice. BMD of male TFam210aMus-/- mice was also reduced, and osteoclast numbers and surface in TFam210aMus-/- mice increased. Microarray analysis of muscle cells from TFam210aMus-/- mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms.

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.

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.

Modulators of Fam210a and Roles of Fam210a in the Function of Myoblasts.

Fam210a is a novel protein regulating muscle mass and strength in mice in vivo. However, detailed effects of Fam210a on the function of myoblasts as well as modulators of Fam210a are still unknown. We, thus, investigated (1) the roles of Fam210a in myoblast differentiation, proliferation, apoptosis and degradation, and (2) the factors that regulate Fam210a expression in murine C2C12 cells. We found that the level of Fam210a mRNA was reduced during myoblast differentiation. Reduction in endogenous Fam210a levels by siRNA suppressed mRNA levels of myogenic factors (Pax7, Myf5, Myogenin, and Mhc) and a muscle degradation factor (Murf1). On the other hand, Fam210a siRNA did not affect mRNA encoding the apoptotic factors Bcl-2 and Bax and the extent of apoptosis as measured by ELISA in C2C12 cells. In contrast, Fam210a siRNA increased the mRNA level of Mmp-12, which induces osteoclastogenesis. Interestingly, insulin and 1,25(OH)2D, which are known to affect cell metabolism and muscle function, significantly increased the level of Fam210a mRNA in a dose-dependent manner. In addition, a PI3-kinase inhibitor and reduction in endogenous levels of the vitamin D receptor (VDR) by siRNA suppressed insulin- and 1,25(OH)2D-induced expression of Fam210a, respectively. In conclusion, Fam210a might enhance myoblast differentiation and proteolysis. Moreover, insulin and 1,25(OH)2D may induce myoblast differentiation and degradation by enhancing the expression of Fam210a.

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.

Depth from phasor distortions in fog.

This paper presents a time-of-flight (ToF) measurement method for use in foggy weather. The depth measured by a ToF camera is greatly distorted in fog because the light scattered in the fog reaches the camera much faster than the target reflection. We reveal that the multi-frequency measurements contain a cue whether two arbitrary pixels have the same depth. After clustering the same depth pixels using this cue, the original depth can be recovered for each cluster by line fitting in the Cartesian coordinate frame. The effectiveness of this method is evaluated numerically via real-world and road-scale experiments.

Bazedoxifene Ameliorates Homocysteine-Induced Apoptosis via NADPH Oxidase-Interleukin 1ß and 6 Pathway in Osteocyte-like Cells.

Homocysteine (Hcy) increases oxidation and inflammation; however, the mechanism of Hcy-induced bone fragility remains unclear. Because selective estrogen modulators (SERMs) have an anti-oxidative effect, SERMs may rescue the Hcy-induced bone fragility. We aimed to examine whether oxidative stress and pro-inflammatory cytokines such as interleukin (IL)-1ß and IL-6 are involved in the Hcy-induced apoptosis of osteocytes and whether bazedoxifene (BZA) inhibits the detrimental effects of Hcy. We used mouse osteocyte-like cell lines MLO-Y4-A2 and Ocy454. Apoptosis was examined by DNA fragmentation ELISA and TUNEL staining, and gene expression was evaluated by real-time PCR. Hcy 5 mM significantly increased expressions of NADPH oxidase (Nox)1, Nox2, IL-1ß, and IL-6 as well as apoptosis in MLO-Y4-A2 cells. Nox inhibitors, diphenyleneiodonium chloride and apocynin, significantly suppressed Hcy-induced IL-1ß and IL-6 expressions. In contrast, an IL-1ß receptor antagonist and an IL-6 receptor monoclonal antibody had no effects on Hcy-induced Nox1 and Nox2 expressions, but significantly rescued Hcy-induced apoptosis. BZA (1 nM-1 µM) and 17ß estradiol 100 nM significantly rescued Hcy-induced apoptosis, while an estrogen receptor blocker ICI 182,780 reversed the effects of BZA and 17ß estradiol. BZA also rescued Hcy-induced apoptosis of Ocy454 cell, and ICI canceled the effect of BZD. Moreover, BZA significantly ameliorated Hcy-induced expressions of Nox1, Nox2, IL-1ß, and IL-6, and ICI canceled the effects of BZA on their expressions. Hcy increases apoptosis through stimulating Nox 1 and Nox 2-IL-1ß and IL-6 expressions in osteocyte-like cells. BZA inhibits the detrimental effects of Hcy on osteocytes via estrogen receptor.

Insulin-Like Growth Factor-I Protects Against the Detrimental Effects of Advanced Glycation End Products and High Glucose in Myoblastic C2C12 Cells.

Previous studies suggested that advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-I) are involved in the mechanism of diabetes-induced sarcopenia. In this study, we examined effects of treatments with AGEs and/or IGF-I for 24 h on myogenic differentiation and apoptosis in mouse myoblastic C2C12 cells. Real-time PCR and Western blot were performed to investigate mRNA and protein expressions, and apoptosis was examined by using a DNA fragment detection ELISA kit. AGE3 significantly decreased mRNA and protein expressions of MyoD and Myogenin, whereas IGF-I significantly increased them and attenuated the effects of AGE3. AGEs significantly decreased endogenous IGF-I mRNA expression and suppressed IGF-I-induced Akt activation. High glucose (22 mM) significantly increased mRNA expression of Rage, a receptor for AGEs, while IGF-I significantly decreased it. DNA fragment ELISA showed that AGE2 and AGE3 significantly increased apoptosis of C2C12 cells, whereas IGF-I significantly suppressed the AGE2- and AGE3-induced apoptosis. In contrast, high glucose enhanced AGE3-induced apoptosis. IGF-I significantly attenuated the effects of high glucose plus AGE3 on the mRNA and protein expressions of MyoD and Myogenin as well as the apoptosis. These findings indicate that AGEs inhibit myogenic differentiation and increase apoptosis in C2C12 cells, and that high glucose increases RAGE and enhances the AGE3-induced apoptosis, suggesting that AGEs and high glucose might contribute to the reduction of muscle mass and function. Moreover, IGF-I attenuated the detrimental effects of AGEs and high glucose in myoblastic cells; thus, IGF-I-Akt signal could be a therapeutic target of DM-induced sarcopenia.

Overweight and underweight are risk factors for vertebral fractures in patients with type 2 diabetes mellitus.

The aim of this cross-sectional study was to examine the association between body mass index (BMI) and the prevalence of vertebral fracture (VF) in Japanese patients with type 2 diabetes (T2DM). A total of 798 patients with T2DM were enrolled. VF was determined semi-quantitatively using lateral X-ray films. The association between BMI quartiles (Q1: ≤ 21.2 kg/m2, Q2: 21.3-23.4 kg/m2, Q3: 23.5-25.8 kg/m2, Q4: 25.9≤ kg/m2) and the presence of VF was examined. Multiple logistic regression analyses adjusted for age, sex, diabetes duration, hemoglobin A1c (HbA1c), estimated glomerular filtration rate, and albumin showed that Q1, Q3, and Q4 were significantly associated with an increased VF risk compared to Q2, which served as a reference [Q1; odds ratio (OR) = 1.91, 95% confidence interval (CI) 1.24-2.95, p = 0.004, Q3; OR = 1.65, 95% CI 1.07-2.55, p = 0.023, and Q4; OR = 2.18, 95% CI 1.39-3.41, p < 0.001]. Moreover, these associations remained significant after additional adjustment for femoral neck T-score, a bone resorption marker, urinary N-terminal cross-linked telopeptide of type-I collagen, and use of insulin and thiazolidinedione. Our study shows for the first time that both overweight and underweight were associated with the bone mineral density (BMD)-independent risk of VF in patients with T2DM. Therefore, body weight control should be considered as a protective measure against diabetes-related bone fragility.

Osteoporosis and vertebral fracture are associated with deterioration of activities of daily living and quality of life in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fracture. However, whether diabetes-related osteoporosis independently contributes to the deterioration of activities of daily living (ADLs) and quality of life (QOL) is unclear. This cross-sectional study investigated the association between osteoporosis, ADLs, and QOL in 309 patients with T2DM. ADLs and QOL were assessed using Barthel Index (BI) and a SF-36 questionnaire. Multiple logistic regression analyses adjusted for age, gender, T2DM duration, body mass index, hemoglobin A1c, estimated GFR, diabetic neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease, and anti-diabetic treatments were conducted. The number of patients with osteoporosis or vertebral fracture was 166 (53.7%) and 118 (38.2%), respectively. Osteoporosis was significantly associated with lower general health (GH), social functioning (SF), and role emotional (RE) (OR 2.56, 1.79, and 1.92, respectively; all p values < 0.05 at least) and marginally associated with lower BI (OR 2.39, p = 0.068). Moreover, the presence of vertebral fracture grade 2 or 3 was significantly associated with lower BI, bodily pain (BP), GH, vitality, SF, and RE (OR 2.58, 2.01, 3.64, 1.99, 2.18, and 1.97, respectively; all p values < 0.05 at least). Osteoporosis and severe vertebral fracture were associated with the deterioration of ADLs and QOL independently of other diabetic complications. Therefore, the management of diabetes-related osteoporosis is an important strategy to avoid the deterioration of ADLs and QOL in T2DM.

Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity.

The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.