In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging.
Very little is known about the signaling pathways mediating vitamin D-induced cell death. A single family of proteases, the caspases, has until recently been considered the pivotal executioner of all programmed cell death (8). Therefore it is interesting to note that breast cancer cells treated with vitamin D compounds die in the complete absence of effector caspase activation (4). Despite the lack of the caspase activation, dying cells present several characteristics of apoptosis, i.e. rounding, shrinkage, and detachment of cells as well as DNA strand breaks and DNA fragmentation (4, 9, 10). Furthermore, antiapoptotic proteins Bcl-2 and Bcl-X L can rescue breast cancer cells from death induced by the active form of vitamin D or its analogs (4). This apoptosis-like death program appears also independent of cysteine cathepsins and p53 tumor suppressor protein (4, 11). Instead, the elevation in the intracellular free calcium ([Ca 2ϩ ] i ) brought about by vitamin D compounds correlates with the induction of apoptosis in breast cancer cells (9,12,13).Data from studies employing various pharmaceutical modulators of calcium homeostasis have suggested that the elevation in [Ca 2ϩ ] i is a sufficient signal to induce apoptosis in several model systems, even though it may also have the opposite effect in other systems (14). Further supporting the idea that the elevation in [Ca 2ϩ ] i may mediate apoptosis, studies based on modulated expression of calcium-binding proteins, calbindin-D 28k or glucose-regulated proteins GRP78 and GRP94, have shown that Ca 2ϩ buffering can confer protection against various apoptotic stimuli (15-19). The calcium-dependent neutral cysteine proteases, calpains, are frequently activated in apoptosis models involving elevated [Ca 2ϩ ] i (20 -22). Two forms of calpains, -calpain and m-calpain or type I and type II calpain, respectively, are ubiquitously expressed in human cells (23)(24)(25). The active forms of the enzymes consist of a variable large subunit (80 kDa) and a common small subunit (30 kDa). To become active, calpains require an elevation in [Ca 2ϩ ] i , and the autoproteolytic cleavage of the enzymes further enhances their activity. Whereas m-calpain requires Ca 2ϩ at a millimolar range, micromolar concentrations are enough for the activation of -calpain (in vitro; lower in cells). So far no difference in the substrate specificity of the two isozymes has been found. Growing evidence suggests that calpains may play a central role in the execution of apoptosis either upstream or * This work was supported by the Danish Medical Research Council, the Danish Cancer Society (to I. S. M. and M. J.), and by Grant CA67317 from the NCI, National Institutes of Health (to I. N. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. § Present address: Molecular Biology, Novo Nordisk A/S, Bagsvaerd DK 2880, Denmar...
Targeting gut microbiota with synbiotics (probiotic supplements containing prebiotic components) is emerging as a promising intervention in the comprehensive nutritional approach to reducing obesity. Weight loss resulting from low-carbohydrate high-protein diets can be significant but has also been linked to potentially negative health effects due to increased bacterial fermentation of undigested protein within the colon and subsequent changes in gut microbiota composition. Correcting obesity-induced disruption of gut microbiota with synbiotics can be more effective than supplementation with probiotics alone because prebiotic components of synbiotics support the growth and survival of positive bacteria therein. The purpose of this placebo-controlled intervention clinical trial was to evaluate the effects of a synbiotic supplement on the composition, richness and diversity of gut microbiota and associations of microbial species with body composition parameters and biomarkers of obesity in human subjects participating in a weight loss program. The probiotic component of the synbiotic used in the study contained Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium longum, and Bifidobacterium bifidum and the prebiotic component was a galactooligosaccharide mixture. The results showed no statistically significant differences in body composition (body mass, BMI, body fat mass, body fat percentage, body lean mass, and bone mineral content) between the placebo and synbiotic groups at the end of the clinical trial (3-month intervention, 20 human subjects participating in weight loss intervention based on a low-carbohydrate, high-protein, reduced energy diet). Synbiotic supplementation increased the abundance of gut bacteria associated with positive health effects, especially Bifidobacterium and Lactobacillus, and it also appeared to increase the gut microbiota richness. A decreasing trend in the gut microbiota diversity in the placebo and synbiotic groups was observed at the end of trial, which may imply the effect of the high-protein low-carbohydrate diet used in the weight loss program. Regression analysis performed to correlate abundance of species following supplementation with body composition parameters and biomarkers of obesity found an association between a decrease over time in blood glucose and an increase in Lactobacillus abundance, particularly in the synbiotic group. However, the decrease over time in body mass, BMI, waist circumstance, and body fat mass was associated with a decrease in Bifidobacterium abundance. The results obtained support the conclusion that synbiotic supplement used in this clinical trial modulates human gut microbiota by increasing abundance of potentially beneficial microbial species.
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