Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study.

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases.

Association between psychomotor function and ALDH2 genotype after consuming barley shochu: A randomized crossover trial.

Sustained exposure to acetaldehyde, the major metabolite of ethanol, may influence psychomotor performance even after the breath ethanol level significantly drops several hours following ethanol consumption. We examined the relationship between psychomotor function and changes in exhaled ethanol and acetaldehyde concentrations after consuming a low dose (0.33 g/kg) of barley shochu, a traditional Japanese distilled alcohol beverage, at the point when the exhaled ethanol concentrations dropped below 78,000 parts per billion (0.

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK-1654, a half-life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo-controlled, single-site, double-blind trial of MK-1654 in 44 healthy Japanese adults.

Recent approaches to gout drug discovery: an update.

Introduction: Inflammation induced by urate deposition in joints causes gout. Healthy individuals maintain serum levels of urate by balancing urate production/excretion, whereas a production/excretion imbalance increases urate levels. Hyperuricemia is diagnosed when the serum urate level is continuously above 7 mg/dl as the solubility limit, and urate accumulates in the kidneys and joints.

Histological evaluation of nintedanib in non-alcoholic steatohepatitis mice.

Aims: In addition to potentially progressing to either cirrhosis or hepatocellular carcinoma, non-alcoholic steatohepatitis (NASH) is currently the leading indication for liver transplantation. Nintedanib has been clinically used to treat idiopathic pulmonary fibrosis for many years, but its effects in an animal model of NASH have not been tested. The purpose of this study was to evaluate the effects of nintendanib on NASH in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-fed mice.

Expression and distribution patterns of spermine, spermidine, and putrescine in rat hair follicle.

No expression and distribution patterns of polyamines (PAs), spermine, spermidine, and their precursor putrescine in mammalian hair follicle are available, although polyamines are known to correlate well with hair growth and epidermal tumor genesis. Immunohistochemistry (IHC) using our original two monoclonal antibodies (mAbs) ASPM-29 specific for spermine or spermidine, and APUT-32 specific for putrescine allowed us to detect immunoreactivity for polyamines in hair follicles from normal adult rats. A wide range of immunoreactivity for the total spermine and spermidine was observed in the compartments of hair follicle: The highest degree of immunoreactivity for polyamines was observed in the matrix, in the Huxley's layer, in the deeper Henle's layer, and in the cuticle of the inner root sheath/the hair cuticle, while moderate immunoreactivity existed in the lower-to-mid cortex and the companion layer, followed by lower immunoreactivity in the outer root sheath, including the bulge region and in the deeper medulla, in which the immunoreactivity was also evident in their nuclei.

Serum levels of genomic DNA of α1(I) collagen are elevated in scleroderma patients.

Recent studies have indicated that various nucleic acids are present in human sera, and attracted attention for their potential as novel disease markers in many human diseases. In this study, we tried to evaluate the possibility that DNA and RNA of collagens exist in human sera, and determined whether their serum levels can be useful biomarkers in scleroderma patients. The RNA or DNA of collagens were purified from sera, and detected by polymerase chain reaction or quantitated by real-time polymerase chain reaction.

Diagnosis of nail psoriasis: evaluation of nail-derived microRNAs as potential novel biomarkers.

Background: MicroRNA levels in sera or hair may potentially be useful biomarkers for various diseases. The diagnosis of nail diseases is sometimes difficult, and nail psoriasis without skin lesions is indistinguishable from nail changes caused by other diseases.

Objectives: We evaluated nail microRNA levels as biomarkers for the diagnosis of psoriasis patients.

Dysregulated interleukin-23 signalling contributes to the increased collagen production in scleroderma fibroblasts via balancing microRNA expression.

Objectives: The overexpression of IL-12 family cytokines is implicated in the pathogenesis of SSc, but their exact role is still unclear. The aim of this study was to investigate the regulation of extracellular matrix expression by IL-23 and its contribution to the phenotype of SSc.

Methods: The mRNA expression was determined by PCR array and real-time PCR.

Establishment and gene expression analysis of disease-derived induced pluripotent stem cells of scleroderma.

Background: We recently generated induced pluripotent stem cells (iPSCs) from cultured dermal fibroblasts of systemic sclerosis (SSc-iPSC) to study the disease mechanisms.

Objective: In the present study, we have performed gene expression analysis using cultured SSc dermal fibroblasts, SSc-iPSC, and fibroblasts re-differentiated from SSc-iPSC (SSc-iPSC-FB).

Methods: mRNA and protein levels of collagen and integrins were analyzed using PCR array, PCR, immunoblotting, and immunofluorescence.

Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts.

Background: Exosomes are small vesicles shed from various cells. They contain proteins, lipids, and nucleic acids, and are regarded as a tool of cell-cell communication.

Objectives: To reveal the putative role of exosomes in systemic sclerosis (SSc), and to elucidate the effect of exosomes on wound healing.

Long non-coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization.

Long non-coding RNAs (lncRNAs) are thought to have various functions other than RNA silencing. We tried to evaluate the expression of lncRNAs in patients with systemic sclerosis (SSc) and determined whether lncRNAs controls collagen expression in dermal fibroblasts. lncRNA expression was determined by real-time PCR and in situ hybridization.

EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin.

IL-12 family cytokines are implicated in the pathogenesis of various autoimmune diseases, but their role in the regulation of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) remain to be elucidated. Among the IL-12 family members, IL-35 decreases type I collagen expression in cultured dermal fibroblasts. IL-35 consists of p35 and EBI3 subunits, and EBI3 alone could downregulate the protein and mRNA expression of type I or type III collagen in the presence or absence of TGF-β costimulation.

Mice overexpressing integrin αv in fibroblasts exhibit dermal thinning of the skin.

Background: Integrins, especially αv integrin (ITGAV), are thought to play central roles in tissue fibrosis and the pathogenesis of scleroderma. So far, skin phenotype of tissue-specific transgenic mice of ITGAV have not been investigated.

Objective: To investigate the role of ITGAV in the skin fibrosis, we engineered transgenic mice that overexpress ITGAV in the fibroblasts under the control of the COL1A2 enhancer promoter.

Decreased interleukin-20 expression in scleroderma skin contributes to cutaneous fibrosis.

Objective: To clarify the role of interleukin-20 (IL-20) in the regulatory mechanism of extracellular matrix expression and to determine the contribution of IL-20 to the phenotype of systemic sclerosis (SSc).

Methods: Protein and messenger RNA (mRNA) levels of collagen, Fli-1, IL-20, and IL-20 receptor (IL-20R) were analyzed using polymerase chain reaction (PCR) array, immunoblotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time PCR.

Results: PCR array revealed that IL-20 decreased gene expression of α2(I) collagen (0.

Hair miR-29a levels are decreased in patients with scleroderma.

In the present study, we evaluated the possibility that we can utilize hair shaft miR-29a levels as disease marker of scleroderma. Hair samples were obtained from 20 scleroderma patients, five dermatomyositis patients and 13 controls. microRNAs were purified from hairs as well as skins or sera, and miR-29a levels were measured with quantitative real-time polymerase chain reaction.

Detection of hair-microRNAs as the novel potent biomarker: evaluation of the usefulness for the diagnosis of scleroderma.

Background: Serum microRNA levels are known as useful biomarkers for various diseases. Recent publication has indicated the existence of microRNAs in hair roots and hair shafts.

Objective: In this study, we evaluated several methods for the extraction of hair microRNAs, and their usefulness for the diagnosis of scleroderma.