KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース)

Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.

Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm

The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

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Mechanisms of NAFLD development and therapeutic strategies

Chromatin immunoprecipitation (ChIP): Revisiting the efficacy of sample preparation and sonication, and of sheared DNA extraction, quantification, and analysis via polymerase chain reaction (PCR)

Ultrasound-mediated drug delivery from microbubbles has been investigated as an alternative therapy for hyper-proliferation of cells connected to the process of restenosis (re-occlusion of blood vessels). In this study, rats underwent arterial balloon injury to induce neointima formation - a hyper-proliferation of smooth muscle cells. High (109) or low (108) doses of microbubbles carrying rapamycin (anti-proliferative drug) were injected via the jugular vein. Acoustic radiation force (1.2 MHz, 65kPa, 100% duty cycle) and contrast-destruction pulses (5MHz, 1.5 MPa, 0.5% duty cycle) were applied focally to enhance drug delivery to the arteries. The addition of acoustic radiation force enhanced drug-mimicking DiI delivery by 90% compared to burst ultrasound alone. Applying both modes of ultrasound using a low dose of microbubbles resulted in a 35.9% reduction in neointima formation, compared to a 34.9% reduction from a high dose of microbubbles without ultrasound. These results validate the ability of ultrasound to provide equivalent drug delivery at 10% of the original dose, and thereby enhancing the “therapeutic window” of targeted drug therapy.

Dual-frequency ultrasound-mediated delivery of rapamycin from microbubbles decreases drug dose needed to reduce neointima formation in vivo

Recapitulation of metabolic defects in models of the urea cycle disorders cps1, otc, ass1, asl, and arg1 using patient-derived primary hepatocytes

The Smooth Muscle Cell-restricted KCNMB1 Ion Channel Subunit Is a Direct Transcriptional Target of Serum Response

An ideal solution for the diagnosis and treatment of a vascular disease must involve high-resolution imaging, quantitative characterization of the lesion, and the means to provide a comprehensive and versatile therapy that can be completed within a single catheterization procedure. Intravascular ultrasound (IVUS) provides real-time, radiation-free imaging and assessment of atherosclerotic disease in terms of anatomical, functional, and molecular information. In this paper we explore the potential of IVUS for diagnosis, therapy, and therapeutic monitoring. In addition, we propose to integrate microfluidic devices directly within a catheter to enable on-demand production of microbubbles for IVUS applications. We have demonstrated that 1) IVUS can perform molecular imaging; 2) IVUS imaging of in situ-produced microbubbles results in a 15 dB increase in lumen contrast; 3) IVUS acoustic radiation force in an ex vivo swine carotid artery model increases delivery of a model drug 17-fold; 4) in situ-produced microbubbles can deliver a model drug to cells under physiologically relevant flows; 5) IVUS in combination with microbubbles can successfully enhance gene delivery in vivo; and 6) IVUS can improve optical methods for estimating model drug delivery.

Brian R. Wamhoff

Papers

Chromatin immunoprecipitation (ChIP): Revisiting the efficacy of sample preparation and sonication, and of sheared DNA extraction, quantification, and analysis via polymerase chain reaction (PCR)

Dual-frequency ultrasound-mediated delivery of rapamycin from microbubbles decreases drug dose needed to reduce neointima formation in vivo

Recapitulation of metabolic defects in models of the urea cycle disorders cps1, otc, ass1, asl, and arg1 using patient-derived primary hepatocytes

The Smooth Muscle Cell-restricted KCNMB1 Ion Channel Subunit Is a Direct Transcriptional Target of Serum Response

Intravascular ultrasound-based imaging and drug delivery