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Therapeutic Angiogenesis for Ischemic Disorders: What Is Missing for Clinical Benefits?

Physical Activity and Aging: A Life-Long Story

Abstract: The benefits of physical activity in preventing premature mortality have been established by a large set of epidemiological studies. These benefits have been shown both in middle-aged and elderly individuals. Furthermore, the reduction of acute events such as myocardial infarction observed with higher levels of physical activity together with the increase in disease-free life expectancy among the most active individuals supports physical activity's anti-aging effect. This review highlights two models supporting this effect. The first model describes the path to frailty and the second explains that immobilization is a stressor which triggers stress-responses responsible for many chronic diseases. Aging reduces the physiological reserve and can lead to frailty when this reserve cannot allow an appropriate adaptation of the aging body to environmental challenges. The components of this physiological reserve can easily be measured by cardiorespiratory testing. Among them are heart rate reserve and VO2max, the maximal body oxygen consumption. The opposite effects of exercise training and aging on the physiological reserve are detailed. Underlying mechanisms of both exercise training and aging are described. Sedentary lifestyle accelerates the effects of aging in susceptible individuals. Sedentary lifestyle induces mechanisms which lead to risk factors of chronic diseases and, eventually, to premature death. These pathological mechanisms and their consequences constitute the sedentary lifestyle syndrome. ... Read more

A Matrix of Cholesterol Crystals, But Not Cholesterol Alone, Primes Human Monocytes/Macrophages for Excessive Endotoxin-induced Production of Tumor Necrosis Factor-Alpha. Role in Atherosclerotic Inflammation?

Abstract: When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower levels of endotoxin were needed for TNF-α production equivalent to that of unprimed cells. The pro-inflammatory effect was selective as endotoxin-induced production of other pro-inflammatory cytokines was unaffected while production of anti-inflammatory interleukin-10 was diminished. These findings suggest that cholesterol matrix formation may play a pathogenic role in atherosclerotic inflammation, and they indicate a mechanism by which bacteria and/or bacterial products may play a role in processes leading to arteriosclerosis. ... Read more

The Participation of Chemokines in Atherosclerosis

Abstract: Chemokines are small protein molecules that play a critical role in immune cell trafficking in the blood vessel lumen and within the blood vessel wall. Three such chemokines are actively involved in atherosclerosis. ... Read more

Identification and Functions of the Plasma Membrane Receptor for Thyroid Hormone Analogues

Abstract: Integrin αvβ3 is a heterodimeric structural protein of the plasma membrane that bears a cell surface receptor for thyroid hormone. The functions of this receptor are distinct from those of the classical nuclear receptor (TR) for thyroid hormone. The integrin is expressed primarily by cancer cells, dividing endothelial and vascular smooth muscle cells, and osteoclasts. The hormone receptor on αvβ3 enables L-thyroxine (T4) and 3, 5, 3'-triiodo-L-thyronine (T3) to stimulate cancer cell proliferation and angiogenesis and to regulate the activity of certain membrane ion pumps. Bound to the receptor, the hormone ligand also stimulates protein trafficking within the cell. A deaminated derivative of T4, tetraiodothyroacetic acid (tetrac), blocks binding and actions of T4 and T3 at the receptor on αvβ3; tetrac also has anti-proliferative actions at the integrin thyroid hormone receptor beyond the effects of antagonizing actions of agonist thyroid hormone analogues at the receptor. The structure-activity relationships of hormone analogues at the receptor have been computer-modeled and indicate that the receptor includes a site that binds T3 and a site that binds both T4 and T3. Mathematical modeling of the kinetics of hormone-binding also suggests the existence of two sites. Cell proliferation is modulated from the T4/T3 site. Tetrac has been re-formulated as a nanoparticle (nanotetrac) that acts exclusively at the αvβ3 receptor and does not enter cells. Nanotetrac disrupts expression of genes in multiple cancer cell survival pathways. The tetrac formulations block human cancer cell proliferation in vitro and in tumor xenografts. Nanotetrac and tetrac inhibit the pro-angiogenic actions in vitro of vascular endothelial growth factor, basic fibroblast factor, and other growth factors. Thus, the receptor described on integrin αvβ3 for T4 and T3, the function of which is materially affected by tetrac and nanotetrac, provides insight into tumor cell biology and vascular biology. ... Read more

Current siRNA Targets in Atherosclerosis and Aortic Aneurysm

Abstract: Atherosclerosis (ATH) and aortic aneurysms (AA) remain challenging chronic diseases that confer high morbidity and mortality despite advances in medical, interventional, and surgical care. RNA interference represents a promising technology that may be utilized to silence genes contributing to ATH and AA. Despite positive results in preclinical and some clinical feasibility studies, challenges such as target/sequence validation, tissue specificity, transfection efficiency, and mitigation of unwanted off-target effects remain to be addressed. In this review the most current targets and some novel approaches in siRNA delivery are being discussed. Due to the plethora of investigated targets, only studies published between 2010 and 2014 were included. ... Read more

Marching Towards Regenerative Cardiac Therapy with Human Pluripotent Stem Cells

Abstract: Damage in cardiac tissues from ischemia or other pathological conditions leads to heart failure; and cell loss or dysfunction in pacemaker tissues due to congenital heart defects, aging, and acquired diseases can cause severe arrhythmias. The promise of successful therapies with stem cells to treat these conditions has remained elusive to the scientific community. However, recent advances in this field have opened new opportunities for regenerative cardiac therapy. Transplantation of cardiomyocytes derived from human pluripotent stem cells has the potential to alleviate heart disease. Since the initial derivation of human embryonic stem cells, significant progress has been made in the generation and characterization of enriched cardiomyocytes and the demonstration of the ability of these cardiomyocytes to survive, integrate, and function in animal models. The scope of therapeutic potential from pluripotent stem cell-derived cardiomyocytes has been further expanded with the invention of induced pluripotent stem cells, which can be induced to generate functional cardiomyocytes for regenerative cardiac therapy in a patient specific manner. The reprogramming technology has also inspired the recent discovery of direct conversion of fibroblasts into cardiomyocyte-like cells, which may allow endogenous cardiac repair. Regenerative cardiac therapy with human pluripotent stem cells is now moving closer to clinic testing. ... Read more

Synthesis of Functional Artificial Lymphoid Tissues

Abstract: The generation of functional artificial lymphoid tissue will be a major focus of future research. In humans, this will be an alternative tool which induces specific immune responses at ectopic sites and offers a novel way to restore the immune status and to treat uncontrollable obstinate diseases such as cancer, autoimmune diseases, severe infection, and immunodeficiency caused by primary defect or aging. Artificially synthesized lymphoid tissue may also provide us with a highly informative method to further study development and physiological functions of lymphoid tissues and organs. We recently reported successful generation of artificial lymph node-like tissues at ectopic sites in mouse. They showed a remarkable ability to induce secondary immune responses upon antigen stimulation, especially when transplanted into naïve or immunodeficient hosts. In this review, before discussing generation of synthetic immune systems, we first summarize previous knowledge on lymphoid development, which provides information valuable for making artificial lymphoid tissues such as spleen and lymph nodes. Then, we discuss problems that need to be solved in order to synthesize artificial lymphoid tissues, including several issues such as combinations of stromal cells, their cell types, soluble factors, and scaffold properties that enable proper accumulation and organization of immune cells in grafts. ... Read more

Dr. Folkman's Pioneering Angiogenesis Research Bears Fruit

Dr. Judah Folkman has a mission: killing cancer cells by starving them. In 1967 at the age of 34, when Dr. Folkman became the youngest professor of surgery at Harvard Medical School, he had already begun formulating the concept of angiogenesis in cancer. In the following 30 years, Dr. Folkman and others documented the importance of angiogenesis in cancer growth and the significance of angiogenesis as a cancer treatment target.

Collectively, these studies formed a powerful thesis for angiogenesis-based cancer therapy. The thesis goes as follows.

1. Tumor growth is dependent on angiogenesis. Microvascular endothelial cells lining the capillaries are essential for ... Read more

Molecular Mechanism of Radiation-Mediated Cancer Cell Death

About a half of all cancer patients receive radiation therapy. The mechanism of radiation-mediated cancer cell death has not been fully elucidated. DNA damage to the cancer cells and p53-mediated apoptotic events have certainly helped in our understanding of the mechanism of radiation therapy.

For radiation therapy to cure a cancer, it has to deal a fatal blow to the last tumor clonogen or tumor stem cell. If one such cell survives and multiplies, the cancer grows back. Solid mass-forming tumor cells depend on the epithelial cells lining the microvascular structures for survival and the continued growth of the solid tumor ... Read more

Oligonucleotides Decoy to NF-kappaB: Becoming a Reality?

Abstract: In the last two decades, frontiers in new drug development are represented by genetic code inhibitors. Nuclear factor-κB (NF-κB) is a transcription factor playing critical roles in many inflammatory/immune diseases. Decoy oligonucleotides (decoy ONs) epitomize an ideal pharmacological tool to selectively block NF-κB activation. Their use is currently being investigated in several chronic inflammatory-based diseases. However, decoy ONs' clinical use is strongly hampered by several issues. Chemical modifications and/or delivery systems have been investigated to overcome some of these limits. This review describes the successful preclinical and clinical applications of decoy ON against NF-κB in inflammatory-based diseases. ... Read more

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