Identification and Characterization of a Novel Dual Inhibitor of Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase.

Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO.

The association of food intake on the development of hearing impairment after middle age among Japanese community dwellers.

Objectives: This study aimed to determine whether food intake modifies the risk of developing hearing impairment (HI) in Japanese adults in their 40s.

Methods: Data for individuals who were in their 40s with no HI at baseline and had participated in the survey multiple times were extracted from the National Institute for Longevity Sciences, Longitudinal Study of Aging. A total of 1846 samples observed for up to 11.

Demonstrative Experiment on the Favorable Effects of Static Electric Field Treatment on Vitamin D-Induced Hypercalcemia.

The purpose of this study was to elucidate the effects of static electric field (SEF) treatment on vitamin D (Vit D)-induced hypercalcemia and renal calcification in mice. The mice were assigned to three groups: Vit D-treated mice, mice treated with Vit D and SEF (Vit D + SEF), and untreated mice. After the administration of Vit D, the Vit D + SEF-treated mice were exposed to SEF treatment by a high-voltage alternating current over five days.

Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors.

A structure-activity relationship study unexpectedly showed that carbonothioates and , obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines and , respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates and cyanocarbonimidodithioates as IDO1 inhibitors. Incorporation of an OH group provided the most potent analogue .

Prostaglandin EP2 receptor downstream of Notch signaling inhibits differentiation of human skeletal muscle progenitors in differentiation conditions.

Understanding the signaling pathways that regulate proliferation and differentiation of muscle progenitors is essential for successful cell transplantation for treatment of Duchenne muscular dystrophy. Here, we report that a γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine tertial butyl ester), which inhibits the release of NICD (Notch intercellular domain), promotes the fusion of human muscle progenitors in vitro and improves their engraftment in the tibialis anterior muscle of immune-deficient mice. Gene expression analysis revealed that DAPT severely down-regulates PTGER2, which encodes prostaglandin (PG) E2 receptor 2 (EP2), in human muscle progenitors in the differentiation condition.

Links Between Physical Frailty and Regional Gray Matter Volumes in Older Adults: A Voxel-Based Morphometry Study.

Objectives: The relationship between physical frailty and regional gray matter volume in the brain was investigated among community-dwelling older Japanese people.

Methods: Participants (N = 835; age range 65-89 years) were community-dwelling older adults in Obu City and Higashiura Town in Aichi Prefecture, Japan. Physical frailty was determined by the modified criteria of the Cardiovascular Health Study, which included weight loss, slowness, weakness, exhaustion, and low physical activity.

Fish and Meat Intake, Serum Eicosapentaenoic Acid and Docosahexaenoic Acid Levels, and Mortality in Community-Dwelling Japanese Older Persons.

The associations between meat/fish consumption, docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) intakes, and blood DHA/EPA levels, and mortality in Japan were examined as part of the National Institute for Longevity Sciences-Longitudinal Study of Aging: 520 men and 534 women (60-79 years at baseline) were followed from 1997-2017. Nutritional intakes were assessed using a 3-day dietary record and fasting venous blood samples were collected. Serum EPA/DHA concentrations, the EPA/arachidonic acid (ARA) ratio, EPA/DHA intakes, and fish/meat intakes were examined in tertiles as indicator variables, and hazard ratios (HR) were calculated to compare the risk of death across tertiles controlling for sex, age, body mass index, smoking status, alcohol drinking, physical activity, education, employment, and history of diseases.

Hearing-impaired elderly people have smaller social networks: A population-based aging study.

Background And Objectives: Hearing impairment (HI) is a major global health concern. In addition, social networks are important for healthy aging. This study aimed to examine the association between HI and social relationships.

Age-related hearing loss and cognitive decline - The potential mechanisms linking the two.

The amount of attention to age-related hearing loss (ARHL) has been growing, not only from the perspective of being one of the most common health conditions affecting older adults, but also from the perspective of its relation to cognition. Results from a number of epidemiological and laboratory studies have demonstrated a significant link between ARHL and cognitive decline. The Lancet International Commission on Dementia, Prevention, Intervention, and Care has estimated that mid-life hearing loss, if eliminated, might decrease the risk of dementia by nine percent, since hearing loss is a modifiable age-associated condition linked to dementia.

Association between Uncoupling Protein 2 Gene Ala55val Polymorphism and Sudden Sensorineural Hearing Loss.

Objectives: The pathology of sudden sensorineural hearing loss, which is known as sudden deafness (SD), remains unknown. The purpose of this study was to investigate the association between mitochondrial uncoupling protein 2 (UCP2) polymorphism and SD risk.

Materials And Methods: We compared 83 patients suffering from SD and 2048 controls who participated in the Longitudinal Study of Aging at the National Institute for Longevity Sciences.

Cyclic analogue of S-benzylisothiourea that suppresses kynurenine production without inhibiting indoleamine 2,3-dioxygenase activity.

Kynurenine is biosynthesised from tryptophan catalysed by indoleamine 2,3-dioxygenase (IDO). The abrogation of kynurenine production is considered a promising therapeutic target for immunological cancer treatment. In the course of our IDO inhibitor programme, formal cyclisation of the isothiourea moiety of the IDO inhibitor 1 afforded the 5-Cl-benzimidazole derivative 2b-6, which inhibited both recombinant human IDO (rhIDO) activity and cellular kynurenine production.

Men who were thin during early adulthood exhibited greater weight gain-associated visceral fat accumulation in a study of middle-aged Japanese men.

Objective: This study aimed to assess the relationship between weight gain from early adulthood and visceral fat accumulation.

Methods: The participants were 549 men aged 42 to 64 years who were randomly selected from the local resident registry for the National Institute for Longevity Sciences' neighbourhood. They were asked to recall their weight at 18 years of age, and then, post-18 weight-change values were calculated for each participant (their current weight minus their weight at 18).

The impact of anthropometric and ocular parameters on optic cup-to-disc ratio.

Background/aims: To assess a relationship between vertical cup--to--disc ratio (VCDR), which is a useful tool to assist in the diagnosis of glaucoma in the early to medium--advanced stages, and intraocular pressure (IOP), central corneal thickness (CCT), body mass index (BMI) and body fat percentage (BFP).

Methods: The data were collected from general populations living in the centre of Japan who had participated in the third wave of the National Institute for Longevity Sciences - Longitudinal Study of Aging. VCDR was set in the general linear mixed model as objective variables with adjustment for age and optic disc area.

What is the best adjustment of appendicular lean mass for predicting mortality or disability among Japanese community dwellers?

Background: Age-related declines in skeletal muscle mass and strength, representing "sarcopenia," are a growing concern in aging societies. However, the prevalence of low muscle mass based on the height-adjustment has been shown to be extremely low, and a more appropriate definition of low muscle mass is needed, particularly for Asian women. The aim of this study was to explore the most appropriate adjustment of appendicular lean mass (ALM) for predicting mortality or disability risk using ALM or any of 5 adjustments of ALM among community-dwelling Japanese.

Inverse Association Between Height-Increasing Alleles and Extreme Longevity in Japanese Women.

Growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/insulin signaling is one of the most plausible biological pathways regulating aging and longevity. Previous studies have demonstrated that several single nucleotide polymorphisms (SNPs) in the GH/IGF-1/insulin signaling-associated genes influence both longevity and adult height, suggesting the possibility of a shared genetic architecture between longevity and height. We therefore examined the relationship between 30 height-associated SNPs and extreme longevity in a Japanese population consisting of 428 centenarians and 4,026 younger controls.

Mechanisms underlying extensive Ser129-phosphorylation in α-synuclein aggregates.

Parkinson's disease (PD) is characterized neuropathologically by intracellular aggregates of fibrillar α-synuclein, termed Lewy bodies (LBs). Approximately 90% of α-synuclein deposited as LBs is phosphorylated at Ser129 in brains with PD. In contrast, only 4% of total α-synuclein is phosphorylated at Ser129 in brains with normal individuals.

Personality and global cognitive decline in Japanese community-dwelling elderly people: A 10-year longitudinal study.

Objectives: To examine the longitudinal associations between the big five personality and changes in global cognitive function among community-dwelling elderly people involved in the National Institute for Longevity Sciences - Longitudinal Study of Aging.

Methods: The participants were 594 individuals (age range 60-81years) and followed for 10years and tested six times. Personality was assessed by the Japanese version of NEO five factor inventory at baseline.

Cognitive abilities predict death during the next 15 years in older Japanese adults.

Aim: The longitudinal relationship between cognitive abilities and subsequent death was investigated among community-dwelling older Japanese adults.

Methods: Participants (n = 1060; age range 60-79 years) comprised the first-wave participants of the National Institute for Longevity Sciences-Longitudinal Study of Aging. Participants' cognitive abilities were measured at baseline using the Japanese Wechsler Adult Intelligence Scale-Revised Short Form, which includes the following tests: Information (general knowledge), Similarities (logical abstract thinking), Picture Completion (visual perception and long-term visual memory) and Digit Symbol (information processing speed).

New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested.

The Longitudinal Impact of Hearing Impairment on Cognition Differs According to Cognitive Domain.

Identification and modification of the risk factors for cognitive decline throughout the adult life span are priority subjects in a progressively aging society; however, much remains to be learned. The aim of this study was to understand whether changes in cognitive function can be affected by hearing impairment (HI) and whether the impact of HI differs depending on the cognitive domain. A total of 1109 individuals aged 60-79 years at baseline who participated in the Longitudinal Study of Aging at the National Institute for Longevity Sciences (NILS-LSA) was followed up for a maximum of 13.

An Oral Aβ Vaccine Using a Recombinant Adeno-Associated Virus Vector in Aged Monkeys: Reduction in Plaque Amyloid and Increase in Aβ Oligomers.

With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable.

Cell-Surface Protein Profiling Identifies Distinctive Markers of Progenitor Cells in Human Skeletal Muscle.

Skeletal muscle contains two distinct stem/progenitor populations. One is the satellite cell, which acts as a muscle stem cell, and the other is the mesenchymal progenitor, which contributes to muscle pathogeneses such as fat infiltration and fibrosis. Detailed and accurate characterization of these progenitors in humans remains elusive.

Dnmt3a Regulates Proliferation of Muscle Satellite Cells via p57Kip2.

Cell differentiation status is defined by the gene expression profile, which is coordinately controlled by epigenetic mechanisms. Cell type-specific DNA methylation patterns are established by chromatin modifiers including de novo DNA methyltransferases, such as Dnmt3a and Dnmt3b. Since the discovery of the myogenic master gene MyoD, myogenic differentiation has been utilized as a model system to study tissue differentiation.