👤 Kenji Ichihara

Carbon nanotubes (CNTs) are important industrial nanomaterials, yet their manufacture presents potential risks for respiratory exposure among workers. CNTs have a high aspect ratio, which raises concerns that they may cause toxicity similar to that of asbestos. Asbestos is known to activate the NLR family pyrin domain containing 3: NLRP3, a key component of inflammasome. We hypothesized that CNTs promote atherosclerosis by enhancing inflammatory response triggered by inflammasome activation. Treatment of human umbilical vein endothelial cells (HUVECs) with two types of double-walled CNTs (DWCNT; NC2150 and NC2100) resulted in a significant increase in the levels of cytoplasmic agglutination of adapter apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) and the levels of phosphorylated ASC and interleukin (IL)-1β. In addition, DWCNT upregulated the expression of adhesion molecule ICAM-1. Consistent with these in vitro findings, apolipoprotein E-deficient (Apoe Show less

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by neurocognitive dysfunction, deposition of amyloid-β (Aβ) plaques, and formation of hyperphosphorylated tau protein. Oxidative stress and neuroinflammation are the main pathological events in AD development. AD is a gender-dependent brain disorder that is predominant in females. Cessation of production of female hormones, such as 17β-estradiol (either due to menopausal or surgical menopause causes), exhibited pro-AD and neurotoxic activities that deteriorate cognitive functions and promote AD development. We investigated the key regulatory role of gender-dependent factors that control the process of AD neuropathogenesis, on the activities of Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, Nuclear factor erythroid 2-related factor 2 (Nrf2), and Apolipoprotein E (APOE). This review aimed to examine the impact of gender-based differences on incidence rates of AD dementia and to reveal the mechanisms regulating the gender differences in AD. In addition, we highlighted the anti-AD activities of sex hormones and the current application of hormonal replacement therapy and estrogen receptor beta-based therapeutic interventions. Furthermore, we presented the impact of gender differences on metabolism in the brain, insulin resistance, and astrocytic activity. Show less

The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC). We performed immune-related gene expression profiling (irGEP) for ALK-rearranged NSCLC to assess the characteristics of the tumor microenvironment and explore potential therapeutic avenues. This study analyzed tumor samples from the ALCURE trial, a prospective observational study examining the efficacy of and mechanisms of resistance to alectinib in patients with ALK-rearranged NSCLC. The irGEP analysis was performed with a panel encompassing 750 immune-related genes. Tumor samples from 52 of the 249 ALCURE trial patients were analyzed. Tumors with high CD8A expression showed upregulation of SNAI1 and downregulation of CDH1, with these genes encoding an epithelial-mesenchymal transition (EMT)-related transcription factor and E-cadherin, respectively, suggestive of EMT progression in these tumors. Tumors with high CD8A expression also manifested downregulation of genes related to tumor angiogenesis, including ANGPT2 (angiopoietin-2) and FLT1 (VEGF receptor 1), suggestive of a quiescent angiogenic state that may facilitate the recruitment of CD8 CD8 Show less

Social interaction with others is essential to life. Although social isolation and loneliness have been implicated as increased risks of cardiometabolic and cardiovascular diseases and all-cause mortality, the cellular and molecular mechanisms by which social connection maintains cardiometabolic and cardiovascular health remain largely unresolved. To investigate how social connection protects against cardiometabolic and cardiovascular diseases, atherosclerosis-prone, high-fat diet-fed These results identify a novel brain-liver axis that links sociality to hepatic lipid metabolism, thus proposing a potential therapeutic strategy for loneliness-associated atherosclerosis progression. Show less

Alzheimer's disease (AD) is the most common cause of dementia in elderly persons. Since the pathology of AD develops slowly from a preclinical or early phase into a fully expressed clinical syndrome, at the time of diagnosis the disease has been progressing for many years. To facilitate the early diagnosis of AD, we performed protein profiling of blood in patients with mild AD as defined by the Functional Assessment Staging (FAST) scale. Plasma samples from mild AD patients and healthy controls were analyzed using two-dimensional differential gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF/MS) followed by peptide mass fingerprinting. Three downregulated proteins were identified: apolipoprotein A-1, alpha-2-HS-glycoprotein, and afamin. Two proteins, including apolipoprotein A-4 and fibrinogen gamma chain, were upregulated in mild AD patients. Our results suggest that altered expression levels of these proteins in plasma may yield candidate biomarkers for the early diagnosis of AD. AD, Alzheimer's disease; FAST, Functional Assessment Staging; 2D-DIGE, two-dimensional differential gel electrophoresis; MALDI-TOF/TOF/MS, matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry; CSF, cerebrospinal fluid; Aβ, amyloid beta; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; NINCDS-ADRDA, National Institute for Neurological Diseases and Stroke/Alzheimer's Disease and Related Disorders Association; CHAPS, 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate; DTT, dithiothreitol; SDS-PAGE, SDS-polyacrylamide gel electrophoresis; DIA, differential in-gel analysis; BVA, biological variation analysis; CBB, Coomassie brilliant blue; 2DE, two-dimensional gel electrophoresis; TFA, trifluoroacetic acid; ACTH, adrenocorticotropic hormone; Apo A-1, apolipoprotein A-1; AHSG, alpha-2-HS-glycoprotein; Apo A-4, apolipoprotein A-4; MCI, mild cognitive impairment. Show less

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes. Show less

The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that directly contributes to high-density lipoprotein (HDL) biogenesis by regulating the cellular efflux of cholesterol. Since ABCA1 plays a pivotal role in cholesterol homeostasis and HDL metabolism, identification of a novel substance that is capable of increasing its expression would be beneficial for the prevention and therapy of atherosclerosis. In the present study, we studied the effects of ethanolic extracts of Brazilian red propolis (EERP) on ABCA1 expression and cholesterol efflux in THP-1 macrophages. EERP enhanced PPARγ and liver X receptor (LXR) transcriptional activity at 5-15μg/ml, which was associated with upregulation of PPARγ and LXRα expression. It was also found that EERP increase the activity of the ABCA1 promoter, which is positively regulated by LXR. Consistent with these findings, treatment with EERP increased both mRNA and protein expression of ABCA1. Finally, EERP upregulated ApoA-I-mediated cholesterol efflux. Our results showed that EERP promote ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression via induction of PPARγ/LXR. Show less

The aetiology of metabolic syndrome is complex, being determined by the interplay of both genetic and environmental factors. The aim of this study was to identify genetic polymorphisms that confer susceptibility to metabolic syndrome, to allow prediction of genetic risk for this condition. The study population comprised 2417 unrelated Japanese subjects (1522 with metabolic syndrome and 895 controls). The genotypes for 44 polymorphisms of 31 candidate genes related to lipid metabolism were determined using a combination of PCR and sequence-specific oligonucleotide probes with suspension array technology. The chi(2) test and subsequent multivariate logistic regression analysis with adjustment for age, sex and smoking status found that the-3A-->G and 553G-->T (Gly185Cys) polymorphisms of APOA5, the 2052T-->C (Val653Val) and 1866C-->T (Asn591Asn) polymorphisms of LDLR, the 13989A-->G (Ile118Val) polymorphism of CYP3A4 and the 1014T-->A polymorphism of C1QTNF5 were significantly (false discovery rate <0.05) associated with the prevalence of metabolic syndrome, with the variant alleles of APOA5 and C1QTNF5 representing risk factors for and those of LDLR and CYP3A4 being protective against this condition. Serum levels of triglycerides and high-density lipoprotein (HDL) cholesterol differed significantly (p<0.05) among APOA5 genotypes; the serum level of HDL cholesterol differed among LDLR genotypes; and the fasting plasma glucose level and body mass index differed between CYP3A4 and C1QTNF5 genotypes, respectively. APOA5, LDLR, CYP3A4 and C1QTNF5 are susceptibility loci for metabolic syndrome in Japanese people. Genotypes for these polymorphisms may prove informative for prediction of genetic risk for metabolic syndrome. Show less

The purpose of the present study was to identify genetic variants that confer susceptibility to dyslipidemia. A total of 5213 individuals from two independent populations were examined: Subject panel A comprised 3794 individuals who visited participating hospitals; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined. The chi(2) test and multivariable logistic regression analysis revealed that seven polymorphisms of APOA5, APOC3, APOA1, ACAT2, and LPL were significantly associated with hypertriglyceridemia, six polymorphisms of APOA5, LIPC, and CYP3A4 with low HDL-cholesterol, and three polymorphisms of APOE and CCR2 with high LDL-cholesterol in subject panel A. For validation of these associations, the same polymorphisms were examined in subject panel B. Six polymorphisms of APOA5, APOC3, APOA1, and LPL were again significantly associated with hypertriglyceridemia, three polymorphisms of APOA5 with low HDL-cholesterol, and two polymorphisms of APOE with high LDL-cholesterol. Serum triglyceride, HDL-cholesterol, and LDL-cholesterol concentrations differed significantly among genotypes of these corresponding polymorphisms in both subject panels. These results indicate that polymorphisms of APOA5, APOC3, APOA1, and LPL are determinants of hypertriglyceridemia and that those of APOA5 and APOE are determinants of low HDL-cholesterol and high LDL-cholesterol, respectively, in Japanese individuals. Show less

The aim of the study was to identify gene polymorphisms that confer susceptibility to metabolic syndrome in order to allow reliable assessment of genetic risk for this condition. The study population comprised 1788 unrelated Japanese individuals (1033 men, 755 women), including 1017 subjects with metabolic syndrome (634 men, 383 women) and 771 controls (399 men, 372 women). The genotypes for 158 polymorphisms of 133 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that the -1131T-->C polymorphism of the apolipoprotein A-V gene (APOA5) was significantly associated with the prevalence of metabolic syndrome, with the C allele representing a risk factor for this condition. A stepwise forward selection procedure demonstrated that APOA5 genotype (CC+TC versus TT) significantly affected the prevalence of metabolic syndrome. The C allele of this polymorphism was associated with an increased serum concentration of triglycerides and a decreased concentration of HDL-cholesterol. Genotype for APOA5 may prove reliable for assessment of genetic risk for metabolic syndrome. Show less

The purpose of the present study was to identify gene polymorphisms for the reliable assessment of genetic factors for obesity. The study population comprised 3906 unrelated Japanese individuals (2286 men, 1620 women), including 1196 subjects (677 men, 519 women) with obesity (body mass index of > or = 25 kg/m2) and 2710 controls (1609 men, 1101 women). The genotypes for 147 polymorphisms of 124 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that the -30Gright curved arrow A polymorphism of GCK, the -240Aright curved arrow T polymorphism of ACE, and the -482Cright curved arrow T polymorphism of APOC3 were significantly (P < 0.01) associated with the prevalence of obesity, and the -1989Tright curved arrow G polymorphism of ESR1 was almost significantly associated. A stepwise forward selection procedure demonstrated that ACE, GCK, and ESR1 genotypes significantly (P < 0.01) and independently affected the prevalence of obesity. Combined genotype analysis for these three polymorphisms yielded a lowest odds ratio of 0.45 for the combined genotypes of AT or TT for ACE, GG for GCK, and GG for ESR1 in comparison with the combined genotypes of AA for ACE, GG for GCK, and TT or TG for ESR1. Genotypes for ACE, GCK, and ESR1 may prove reliable for the assessment of genetic factors for obesity. Determination of the combined genotypes for these genes may contribute to the personalized prevention of this condition. Show less