Catálogo de publicaciones - libros

A series of studies have revealed that IL-6 has pleiotropic activity in various cells and that its deregulated expression is responsible for the development of multiple autoimmune inflammatory diseases. A humanized antibody against the IL-6 receptor, tocilizumab, has exhibited outstanding therapeutic efficacy against rheumatoid arthritis, juvenile idiopathic arthritis, Castleman’s disease, and other autoimmune inflammatory diseases, leading to its clinical use for treatment of several diseases. These findings indicate that overproduction of IL-6 is responsible for the pathogenesis of autoimmune inflammatory diseases, in which an imbalance between Th17 cells and regulatory T cells and autoantibodies play central roles. Recent studies have suggested that IL-6 blockade therapy can rectify these underlying immunological abnormalities in autoimmunity. However, the causes of deregulated IL-6 production in these diseases remain unknown. A novel IL-6-regulating molecule, Arid5a, specifically stabilizes IL-6 mRNA and sustains its overproduction; thus, Arid5a plays an important role in promoting inflammation and autoimmune diseases. Indeed, in Arid5a-knockout mice, experimental autoimmune encephalomyelitis does not develop, and lipopolysaccharide stimulation does not induce elevated expression of IL-6. Arid5a can counteract the destabilizing effect of a regulatory RNase, Regnase-1, on IL-6 mRNA; Regnase-1 knockout mice spontaneously develop various fatal autoimmune diseases. Further analyses of these RNA-binding proteins as well as other regulatory molecules for IL-6 expression are expected to elucidate the molecular mechanisms underlying deregulated synthesis of IL-6, and facilitate investigations of the pathogenesis of specific diseases.

Non-alcoholic steatohepatitis (NASH) is closely associated with progression to liver cirrhosis and hepatocellular carcinoma. We reported that melanocortin 4 receptor–deficient mice (MC4R-KO mice), when fed a high-fat diet, provide a novel rodent model of NASH. Recently, we have identified a unique histological feature termed “hepatic crown-like structures” (hCLS) in the livers of MC4R-KO mice and NASH patients. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, similar to the “crown-like structure (CLS)” described in obese adipose tissue. Interestingly, we have recently reported that macrophage-induced C-type lectin (Mincle) is involved in CLS formation and fibrogenic gene expression in obese adipose tissue, suggesting the pathophysiologic role of CLS in obesity-induced adipose tissue fibrosis. Collectively, our data provide evidence that hCLS serves as an origin of hepatic inflammation and fibrosis during the progression from simple steatosis to NASH and thus helps in elucidation of the pathogenesis of NASH, pursuit of specific biomarkers, and evaluation of potential therapeutic strategies.

This is a short summary of my presentation in the Uehara Memorial Foundation Symposium 2014. Classification of mental illness in current diagnostic systems [such as the (DSM)] is built on clinical reliability and utility, but not on etiological validity. Thus, the DSM has not provided an ideal classification of mental disorders. To overcome the dilemma, the National Institute of Mental Health (NIMH) recently proposed the Research Domain Criteria (RDoC) framework. This new framework emphasizes a dimensional approach on the basis of neurocircuitry mechanism. There were three aims in my presentation. First, I summarized the concept of research strategies on the basis of dimensional approach, with a link to the trajectory from early development to adolescence in the disease pathology. Second, I introduced an example of a research infrastructure that could support translational and clinical study for mental illness. Third, I showed two studies that were utilizing the infrastructure.

Leptin, an adipocyte-derived hormone, plays crucial roles in the regulation of energy expenditure and food intake. Through analyses of leptin transgenic mice, we have demonstrated that leptin has pleiotropic effects such as regulation of insulin sensitivity and lipid metabolism. Lipodystrophy is a disease characterized by a lack of adipose tissue, which leads to metabolic disorders including insulin resistant diabetes, hypertriglyceridemia, and fatty liver. We demonstrated that leptin deficiency plays an important role in the pathogenesis of metabolic disorders in lipodystrophy. We also demonstrated the efficacy of leptin replacement therapy in lipodystrophy. Leptin improves insulin sensitivity at least partly by cancellation of lipotoxicity in the liver and skeletal muscle. It is also possible that leptin improves insulin secretion by cancellation of lipotoxicity in pancreatic beta cells. Using animal models, we demonstrated that leptin activates hepatic AMP-activated protein kinase (AMPK), and hepatic AMPK activation is involved in the therapeutic effects of leptin. To elucidate the pathogenic mechanism of hyperphagia in lipodystrophy, we measured food-related neural activity by fMRI and investigated subjective feelings of appetite. We found insufficiency of postprandial suppression of food-related neural activity and formation of satiety feelings in patients with lipodystrophy, which might be largely due to leptin deficiency. In March 2013, marketing and manufacturing approval was granted for metreleptin for the treatment of lipodystrophy in Japan on the basis of the results of our investigator-initiated trial. This is the first global approval of leptin formulation. Leptin has potential as a drug for the treatment of more common metabolic diseases including diabetes, hyperlipidemia, and fatty liver.

The natriuretic peptide family consists of three endogenous ligands: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They exert their biological actions through two subtypes of particulate guanylyl cyclase (GC): GC-A for ANP and BNP, and GC-B for CNP. Among the natriuretic peptide family members, ANP and BNP are cardiac hormones that are produced and released from the atrium and ventricle of the heart, respectively, and play important roles in the regulation of the cardiovascular system. On the other hand, although CNP and its receptor, GC-B, exist ubiquitously in the body, we elucidated that the CNP/GC-B system is a crucial stimulator of endochondral bone growth, using CNP or GC-B knockout or transgenic mice. We planned to utilize the activation of the CNP/GC-B pathway as a novel therapeutic strategy for skeletal dysplasia, which consists of multiple skeletal diseases including those with impaired bone growth. We tried to investigate this effect on impaired skeletal growth in a mouse model of achondroplasia, the most common form of skeletal dysplasias, and successfully recovered the skeletal phenotype by using transgenic technology or by administration of synthetic CNP. In the future, the activation of the CNP/GC-B system may constitute a novel therapeutic strategy for the treatment of skeletal dysplasias.

The tremendous progress in understanding the mechanisms of tissue fibrosis has led to realistic hopes for effective antifibrotic therapies in a range of diseases, including hepatic fibrosis, idiopathic pulmonary fibrosis, and renal fibrosis, as well as fibrotic disorders of muscle, heart, skin and bone marrow. Common mechanisms across these different tissues have unearthed targets that may be relevant to many organs. Best understood are pathways leading to hepatic fibrosis, which also predispose to hepatocellular carcinoma. Hepatic stellate cells are the principal fibrogenic cells in the liver following their activation into myofibroblasts, and their detailed characterization has unearthed many targets for therapy. Increasingly, investigators now rely on genetic mouse models to define contributions of specific molecules, in hopes of antagonizing these molecules as therapeutic targets. Both genomic and molecular approaches are unveiling new patterns of gene expression and molecules. A robust framework for antifibrotic drug discovery has been developed, and many agents are in clinical trials. With iterative evaluation of drug candidates in both animal models and humans, accelerated progress in bringing these drugs to patients is anticipated.

The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors as well as signal integrators. Several members of the TRP family are sensitive to changes in cellular redox status. Among them, TRPA1 is remarkably susceptible to various oxidants and is known to mediate neuropathic pain and respiratory, vascular, and gastrointestinal functions, making TRPA1 an attractive therapeutic target. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. Most recently, we found that a novel -nitrosamine compound activates TRPA1 by -nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol) and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the -nitrosamine. On the other hand, TRPCs are typical receptor-activated Ca-permeable cation channels, which sense messenger molecules generated downstream of phospholipase activation. Previously, activation of TRPC3 and TRPC6 by diacylglycerol has been reported to play important roles in the pathogenesis of cardiac hypertrophy. Also, a pyrazole compound, Pyr3, which selectively inhibits TRPC3, suppresses cardiac hypertrophy in animal models in vitro and in vivo. We have most recently found that Pyr3 and related compounds are effective in suppressing cardiac fibrosis and ischemia responsible for cardiac remodeling as well. Thus, in this chapter, we describe the molecular pharmacology of TRP modulators and discuss their modulatory mechanisms and pharmacological actions.

Autophagy usually functions in cell-protective events. However, it may also be utilized as a cell-suicide mechanism, which is known as “autophagic cell death.” Autophagic cell death is frequently induced in cells that lack apoptotic machinery, such as p53-deficient cancer cells. Therefore, small compounds that activate autophagic cell death are good candidates for anticancer chemotherapeutics to combat p53-deficient cancers. This chapter focuses on recent advances in autophagy/autophagic cell death and their relationship with tumorigenesis.

Adrenomedullin (AM) was originally isolated from human pheochromocytoma as a biologically active peptide with potent vasodilating action, but it also has a wide range of physiological properties including cardiovascular protection, neovascularization, and the ability to suppress apoptosis. It is constitutively produced by various tissues including the gastrointestinal tract. AM production and secretion can be induced by pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1, as well as by lipopolysaccharide. Conversely, AM causes the downregulation of inflammatory cytokines in cultured cells and downregulates inflammatory processes in various models of colitis, including those induced by acetic acid and by dextran sulfate sodium. AM works by exerting anti-inflammatory and antibacterial effects and by stimulating mucosal regeneration and supporting maintenance of the colonic epithelial barrier. The present findings suggest that AM could serve as a novel agent for treating refractory ulcerative colitis.

The ability to manipulate gene expression is invaluable for understanding the molecular pathogenesis of disease as well as for developing novel therapeutics. RNA interference provides a robust platform for the knockdown of a specific gene at the post-transcriptional level, but activation of specific genes traditionally has been limited to ligand-mediated activation of signal transduction pathways or introduction of exogenous transgenes from expression vectors. Recent work has shown that small RNA molecules targeted to the promoter region of a gene can activate gene expression. This phenomenon, called RNA activation, provides a tool for specific activation of endogenous genes, and introduces a new role for noncoding RNAs in the regulation of gene expression. These small RNAs are typically 21-nucleotide duplexes, and have been shown to activate a wide variety of genes in many cell types and across species. The application of this technology will prove invaluable for basic research through gain-of-function studies and potentially targeted gene activation for disease intervention. This chapter will cover what is currently defined on the mechanism of RNA activation, and will explore the possible application of this technology for novel therapeutics.