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The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3 or calcitriol), is known to inhibit the proliferation and invasiveness of many types of cancer cells, including breast, colon, pancreatic, prostate, and liver cancer cells. These findings support the use of 1α,25(OH)2D3 for the treatment of these types of cancer. However, 1α,25(OH)2D3 can cause hypercalcemia, so analogs of 1α,25(OH)2D3 that are less calcemic but exhibit more potent anti-tumor activity would be good candidates as therapeutic agents. Therefore, a series of 19-norvitamin D analogs, in which the methylidene group on C19 is replaced with 2 hydrogen atoms, have been synthesized by several laboratories. In our laboratory, we have designed and synthesized a series of 2α-functional group substituted 19-norvitamin D3 analogs and examined their anti-proliferative activity. Among them, 2α- and 2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3 (MART-10 and MART-11) were found to be the most promising. Here, we review the rationale and approaches for the synthesis of different 19-norvitamin D analogs, and the pre-clinical studies using these analogs in breast cancer cells, in particular, we chose MART-10 for its potential application to the prevention and treatment of breast cancer. [ABSTRACT FROM AUTHOR]

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Voltage clamp fluorimetry (VCF) utilizes fluorescent probes that covalently bind to cysteine residues introduced into proteins and emit light as a function of their environment. Measurement of this emitted light during membrane depolarization reveals changes in the emission level as the environment of the labelled residue changes. This allows for the correlation of channel gating events with movement of specific protein moieties, at nanosecond time resolution. Since the pioneering use of this technique to investigate Shaker potassium channel activation movements, VCF has become an invaluable technique used to understand ion channel gating. This review summarizes the theory and some of the data on the application of the VCF technique. Although its usage has expanded beyond voltage-gated potassium channels and VCF is now used in a number of other voltage- and ligand-gated channels, we will focus on studies conducted in Shaker potassium channels, and what they have told us about channel activation and inactivation gating. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases and cancer (especially lung cancer) are leading causes of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Some have implicated systemic inflammation, which is commonly observed in COPD, as the potential mechanistic bridge between COPD and these disorders. This concept has been supported by animal studies especially in rabbits, which have clearly demonstrated the effect of local lung inflammation on systemic inflammation and on the progression of atherosclerosis and by cross-sectional population-based studies, which have shown a significant relationship between systemic inflammation, as measured by circulating C-reactive protein (CRP) and the risk of cardiovascular diseases in COPD patients. These data have been further extended by a recent study that has elucidated the temporal nature of the relationship between systemic inflammation and the risk of cardiovascular events and cancer in COPD patients. This study showed that baseline CRP levels predicted the incidence of cardiovascular events and cancer-specific mortality over 7 to 8 years of follow-up. CRP levels also predicted all-cause mortality. Collectively, these data indicate that systemic inflammation may play an important role in mediating the extra-pulmonary complications of COPD. Systemic inflammation may contribute substantially to the overall morbidity and mortality of COPD patients. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a multifactor, highly complex disease with numerous aetiologies that work synergistically to promote lesion development. One of the emerging components that drive the development of both early- and late-stage atherosclerotic lesions is the participation of both the innate and acquired immune systems. In both humans and animal models of atherosclerosis, the most prominent cells that infiltrate evolving lesions are macrophages and T lymphocytes. The functional loss of either of these cell types reduces the extent of atherosclerosis in mice that were rendered susceptible to the disease by deficiency of either apolipoprotein E or the LDL (low density lipoprotein) receptor. In addition to these major immune cell participants, a number of less prominent leukocyte populations that can modulate the atherogenic process are also involved. This review will focus on the participatory role of two “less prominent” immune components, namely natural killer (NK) cells and natural killer T (NKT) cells. Although this review will highlight the fact that both NK and NKT cells are not sufficient for causing the disease, the roles played by both these cells types are becoming increasingly important in understanding the complexity of this disease process. [ABSTRACT FROM AUTHOR]

Neonatal circulatory transition is dependent upon tightly regulated pulmonary circuit relaxation. Persistent pulmonary hypertension (PPHN), a rapidly progressive disease of pulmonary arterial vasospasm and remodelling, may be characterized by pulmonary arterial myocyte relaxation failure. A key regulator of vascular tone is myocyte calcium sensitivity, determined by the relative stoichiometry of myosin light chain phosphorylation and dephosphorylation. We have recently reported downregulation of myosin light chain phosphatase activity in a hypoxic model of neonatal pulmonary hypertension. This review examines the recognized pathways of regulation governing myosin light chain phosphatase activity, including targeting subunit isoform switching, targeting unit phosphorylation and catalytic site inhibition. In light of the reviewed literature, further speculation is proposed on the potential contributions of these mechanisms to the pathophysiology of the perinatal pulmonary arterial relaxation defect in PPHN. [ABSTRACT FROM AUTHOR]