Vitamin D and Physical Activity

Vitamin D is synthesized in the skin following exposure to ultraviolet radiation, producing cholecalciferol, while only a small percentage of the circulating vitamin D is of exogenous origin deriving from food. Following two sequential hydroxylations, in the liver and in the kidneys, vitamin D is fully activated. Although its role in bone physiology and calcium homeostasis is well documented, there is emerging evidence that vitamin D exerts a plethora of additional effects on most tissues regulating the musculoskeletal, cardiovascular, and immune systems as well as energy homeostasis. Its deficiency/insufficiency poses a major public health problem observed in all age groups and regardless of latitude and insolation. In muscles, vitamin D deficiency is associated with a decline in neuromuscular function including muscular strength, walking speed, balance, jumping and sprinting performance, and aerobic capacity, although the evidence is still weak regarding its effects in the young and the athletes. Supplementation counteracts the negative effects of vitamin D deficiency on performance although in individuals with adequate levels of vitamin D, additional supplementation does not appear to enhance further physical capabilities. The aim of this chapter is to review our current understanding of diverse effects of vitamin D in physical performance in athletic and nonathletic populations

Interaction of heat shock protein (hsp90) with the cytoskeleton: potential implication in intracellular transport

In this article we will summarize the details concerning the association of 90kD heat shock protein (hsp90) with cytoskeletal structures and we will discuss the potential involvement of these interactions in the translocation of steroid hormone receptors to the cell nucleus. In cultured mammalian cells hsp90 has been found to be colocalized with both microtubules and cytokeratin intermediate filaments, whereas no association with actin filaments and vimentin intermediate filaments has been established. The colocalization of hsp90 with microtubules and cytokeratin in intact cells rises the possibility that cytoskeletal structures could serve as "rails" for the direct movement of the steroid hormone receptor via association-dissociation with hsp90 molecules from the cytoplasmic site of synthesis to the nuclear site of action.Biomedical Reviews 1994; 3: 27-37

Opioid peptides in the female reproductive system: physiological implications

All endogenous opioid peptides derive from three precursor molecules i.e. proopiomelanocortin, proenkephalin and prodynorphin. The endogenous opioid peptides exert their biological effects through opioid receptors. Each endogenous opioid peptide exhibits higher binding affinity towards a specific type of opioid receptors. Current evidence suggests that endogenous opioid peptides play important regulatory roles in reproduction. Endogenous opioid peptides are present through the hypothalamic-pituitary-gonadal axis. The hypothalamic opioidergic mechanism represents one of the important central control systems of gonadotropin-releasing hormone and gonadotropin release. Opioids mediate the sex steroid effect exerted on gonadotropin-releasing hormone and luteinizing hormone secretion and play a crucial role in the integration of several neuroendocrine mechanisms. There is also evidence that suprahypothalamic mechanism enhances endogenous opioid inhibition of gonadotropin-releasing hormone. The genes of the endogenous opioid peptides are also expressed in peripheral reproductive tissues such as the endometrium and placenta. At least part of the endogenous opioid peptides effects may be paracrine or autocrine in nature. The possible roles of opioids in various physiological processes of the female reproductive system are also reviewed.Biomedical Reviews 1995; 4: 71-83

Expression of the Tpl2/Cot oncogene in human T-cell neoplasias

BACKGROUND: Tpl2/Cot oncogene has been identified in murine T-cell lymphomas as a target of MoMuLV insertion. Animal and tissue culture studies have shown that Tpl2/Cot is involved in interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) production by T-cells contributing to T-cell proliferation. In the present report we examined a series of 12 adult patients with various T-cell malignancies, all with predominant leukemic expression in the periphery, for the expression of Tpl2/Cot oncogene in order to determine a possible involvement of Tpl2/Cot in the pathogenesis of these neoplasms. RESULTS: Our results showed that Tpl2/Cot was overexpressed in all four patients with Large Granular Lymphocyte proliferative disorders (LGL-PDs) but in none of the remaining eight patients with other T-cell neoplasias. Interestingly, three of the LGL-PD patients displayed neutropenia, one in association with sarcoidosis. Serum TNF-α levels were increased in all Tpl2/Cot overexpressing patients while serum IL-2 was undetectable in all subjects studied. Genomic DNA analysis revealed no DNA amplification at the Tpl2/Cot locus in any of the samples analyzed. CONCLUSIONS: We conclude that Tpl2/Cot, a gene extensively studied in animal and tissue culture T-cell models may be also involved in the development of human LGL-PD and may have a role in the pathogenesis of immune manifestations associated with these diseases. This is the first report implicating Tpl2/Cot in human T-cell neoplasias and provides a novel molecular event in the development of LGL-PDs

Advanced Modalizing Problems

I present an internal problem for David Lewis’s genuine modal realism. My aim is to show that his analysis of modality is inconsistent with his metaphysics. I consider several ways of modifying the Lewisian analysis of modality, but argue that none are successful. I argue that the problem also affects theories related to genuine modal realism, including the stage theory of persistence and modal fictionalism

The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress

<p>Abstract</p> <p>Introduction</p> <p>Stress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF) is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo.</p> <p>Methods</p> <p>For this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis.</p> <p>Results</p> <p>Array analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this effect. Moreover, antalarmin suppressed neoangiogenesis in 4T1 tumors in vivo.</p> <p>Conclusion</p> <p>This is the first report demonstrating that peripheral CRF, at least in part, mediates the tumor-promoting effects of stress and implicates CRF in SMAD2 and β-catenin expression.</p

Sex steroids and personality traits in the middle luteal phase of healthy normally menstruating young professional women

.10, F(1,57)=6.23, p=0.016). We were unable to find any association between the circulating androgens and scores on the masculinity-femininity scale (Mf). We were also unable to document any association between the weak adrenal androgens DHEA and DHEA-S and depression in contrast to several published reports. (c) Our data suggest a marginally significant association between progesterone and scores on the 7-Pt (obsessive/compulsive/psychasthenia) scale (r=0.27, p&lt;0.05). However, only 7% of the 7-Pt variance was explained by progesterone (r 2 =0.071, F(1,50)=3.81, p=0.057). cONcluSIONS: We have found that total testosterone was associated with the paranoia score, the metabolic product of activated androgens, 3alpha-diolG, to social introversion and, finally, progesterone to obsessive-compulsive behavior

A Novel Role of Peripheral Corticotropin-Releasing Hormone (CRH) on Dermal Fibroblasts

Corticotropin-releasing hormone, or factor, (CRH or CRF) exerts important biological effects in multiple peripheral tissues via paracrine/autocrine actions. The aim of our study was to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing. We show expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh−/−) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF1 antagonist antalarmin recapitulated the findings in the Crh−/− cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6. In conclusion, our findings show an important role of fibroblast-expressed CRH in the proliferation, migration, and cytokine production of these cells, processes associated with the skin response to injury. Our data suggest that the immunomodulatory effects of CRH may include an important, albeit not explored yet, role in epidermal tissue remodeling and regeneration and maintenance of tissue homeostasis

Corticotropin-Releasing Hormone Augments Proinflammatory Cytokine Production from Macrophages In Vitro and in Lipopolysaccharide-Induced Endotoxin Shock in Mice

Corticotropin-releasing hormone (CRH) exerts an anti-inflammatory effect indirectly, via cortisole production, and a proinflammatory effect directly on immune cells. The aim of the present work was to examine the effect of CRH on macrophage-derived cytokines both in vitro and in vivo. For the in vitro experiments we used two types of macrophages: (i) the RAW264.7 monocyte/macrophage cell line and (ii) thioglycolate-elicited peritoneal macrophages from BALB/c mice. We have found that CRH enhanced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 production. For the in vivo experiments we have used the LPS-induced endotoxin shock model in BALB/c mice, an established model for systemic inflammation in which macrophages are the major source of the proinflammatory cytokines responsible for the development of the shock. Administration of antalarmin, a synthetic CRH receptor 1 (CRHR1) antagonist, prior to LPS prolonged survival in a statistically significant manner. The effect was more evident at the early stages of endotoxin shock. CRHR1 blockade suppressed LPS-induced elevation of the macrophage-derived cytokines TNF-α, IL-1β, and IL-6, confirming the role of CRH signals in cytokine expression. In conclusion, our data suggest that CRH signals play an early and crucial role in augmenting LPS-induced proinflammatory cytokine production by macrophages. Our data suggest that the diffuse neuroendocrine system via CRH directly affects the immune system at the level of macrophage activation and cytokine production