Curcumin (diferuloylmethane), a polyphenol extracted from the plant Curcuma longa, is widely used in
Southeast Asia, China and India in food preparation and for medicinal purposes. Since the second ...half of the last century,
this traditional medicine has attracted the attention of scientists from multiple disciplines to elucidate its pharmacological
properties. Of significant interest is curcumin?s role to treat neurodegenerative diseases including Alzheimer?s disease
(AD), and Parkinson?s disease (PD) and malignancy. These diseases all share an inflammatory basis, involving increased
cellular reactive oxygen species (ROS) accumulation and oxidative damage to lipids, nucleic acids and proteins. The
therapeutic benefits of curcumin for these neurodegenerative diseases appear multifactorial via regulation of transcription
factors, cytokines and enzymes associated with (Nuclear factor kappa beta) NFκB activity. This review describes the
historical use of curcumin in medicine, its chemistry, stability and biological activities, including curcumin's anti-cancer,
anti-microbial, anti-oxidant, and anti-inflammatory properties. The review further discusses the pharmacology of
curcumin and provides new perspectives on its therapeutic potential and limitations. Especially, the review focuses in
detail on the effectiveness of curcumin and its mechanism of actions in treating neurodegenerative diseases such as
Alzheimer?s and Parkinson?s diseases and brain malignancies.
The prevalence of vitamin D deficiency varies, with the groups at greatest risk including housebound, community‐dwelling older and/or disabled people, those in residential care, dark‐skinned people ...(particularly those modestly dressed), and other people who regularly avoid sun exposure or work indoors.
Most adults are unlikely to obtain more than 5%–10% of their vitamin D requirement from dietary sources. The main source of vitamin D for people residing in Australia and New Zealand is exposure to sunlight.
A serum 25‐hydroxyvitamin D (25‐OHD) level of ≥ 50 nmol/L at the end of winter (10–20 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal musculoskeletal health.
Although it is likely that higher serum 25‐OHD levels play a role in the prevention of some disease states, there is insufficient evidence from randomised controlled trials to recommend higher targets.
For moderately fair‐skinned people, a walk with arms exposed for 6–7 minutes mid morning or mid afternoon in summer, and with as much bare skin exposed as feasible for 7–40 minutes (depending on latitude) at noon in winter, on most days, is likely to be helpful in maintaining adequate vitamin D levels in the body.
When sun exposure is minimal, vitamin D intake from dietary sources and supplementation of at least 600 IU (15 μg) per day for people aged ≤ 70 years and 800 IU (20 μg) per day for those aged > 70 years is recommended. People in high‐risk groups may require higher doses.
There is good evidence that vitamin D plus calcium supplementation effectively reduces fractures and falls in older men and women.
Sunlight vitamin D and skin cancer Mason, Rebecca S; Reichrath, Jörg
Anti-cancer agents in medicinal chemistry
13, Številka:
1
Journal Article
Recenzirano
Today, there is a controversial debate in many scientific and public communities on how much sunlight is appropriate to balance between the positive and negative effects of solar UV-exposure. UV ...exposure undoubtedly causes DNA damage of skin cells and is a major environmental risk factor for all types of skin cancers. In geographic terms, living in parts of the world with increased erythemal UV or high average annual bright sun results in increased risks of skin cancers, with the greatest increased risk for squamous cell carcinoma, followed by basal cell carcinoma and then melanoma. On the other hand, sunlight exerts positive effects on human health, that are mediated in part via UV-B-mediated cutaneous photosynthesis of vitamin D. It has been estimated that at present, approximately 1 billion people worldwide are vitamin D-deficient or -insufficient. This epidemic causes serious health problems that are still widely under-recognized. Vitamin D deficiency leads to well documented problems for bone and muscle function. There are also associations between vitamin D-deficiency and increased incidence of and/or unfavourable outcome for a broad variety of independent diseases, including various types of malignancies (e.g. colon-, skin-, and breast cancer), autoimmune diseases, infectious diseases, and cardiovascular diseases. In this review, the present literature is analyzed to summarize our present knowledge about the important relationship of sunlight, vitamin D and skin cancer.
Vitamin D deficiency is associated with a range of muscle disorders, including myalgia, muscle weakness, and falls. In humans, polymorphisms of the vitamin D receptor (VDR) gene are associated with ...variations in muscle strength, and in mice, genetic ablation of VDR results in muscle fiber atrophy and motor deficits. However, mechanisms by which VDR regulates muscle function and morphology remain unclear. A crucial question is whether VDR is expressed in skeletal muscle and directly alters muscle physiology. Using PCR, Western blotting, and immunohistochemistry (VDR-D6 antibody), we detected VDR in murine quadriceps muscle. Detection by Western blotting was dependent on the use of hyperosmolar lysis buffer. Levels of VDR in muscle were low compared with duodenum and dropped progressively with age. Two in vitro models, C2C12 and primary myotubes, displayed dose- and time-dependent increases in expression of both VDR and its target gene CYP24A1 after 1,25(OH)2D (1,25 dihydroxyvitamin D) treatment. Primary myotubes also expressed functional CYP27B1 as demonstrated by luciferase reporter studies, supporting an autoregulatory vitamin D-endocrine system in muscle. Myofibers isolated from mice retained tritiated 25-hydroxyvitamin D3, and this increased after 3 hours of pretreatment with 1,25(OH)2D (0.1nM). No such response was seen in myofibers from VDR knockout mice. In summary, VDR is expressed in skeletal muscle, and vitamin D regulates gene expression and modulates ligand-dependent uptake of 25-hydroxyvitamin D3 in primary myofibers.
The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino ...acids,
-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca
) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca
homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca
homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca
, an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G
, G
, potentially G
, and even G
in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. SIGNIFICANCE STATEMENT: The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.
Sclerostin is an important regulator of bone homeostasis and canonical Wnt signaling is a key regulator of osteogenesis. Strontium ranelate is a treatment for osteoporosis that has been shown to ...reduce fracture risk, in part, by increasing bone formation. Here we show that exposure of human osteoblasts in primary culture to strontium increased mineralization and decreased the expression of sclerostin, an osteocyte-specific secreted protein that acts as a negative regulator of bone formation by inhibiting canonical Wnt signaling. Strontium also activated, in an apparently separate process, an Akt-dependent signaling cascade via the calcium-sensing receptor that promoted the nuclear translocation of β-catenin. We propose that two discrete pathways linked to canonical Wnt signaling contribute to strontium-induced osteogenic effects in osteoblasts.
Vitamin D, unlike the micronutrients, vitamins A, E, and K, is largely obtained not from food, but by the action of solar ultraviolet (UV) light on its precursor, 7-dehydrocholesterol, in skin. With ...the decline in UV light intensity in winter, most skin production of vitamin D occurs in summer. Since no defined storage organ or tissue has been found for vitamin D, it has been assumed that an adequate vitamin D status in winter can only be maintained by oral supplementation. Skeletal muscle cells have now been shown to incorporate the vitamin D-binding protein (DBP) from blood into the cell cytoplasm where it binds to cytoplasmic actin. This intracellular DBP provides an array of specific binding sites for 25-hydroxyvitamin D (25(OH)D), which diffuses into the cell from the extracellular fluid. When intracellular DBP undergoes proteolytic breakdown, the bound 25(OH)D is then released and diffuses back into the blood. This uptake and release of 25(OH)D by muscle accounts for the very long half-life of this metabolite in the circulation. Since 25(OH)D concentration in the blood declines in winter, its cycling in and out of muscle cells appears to be upregulated. Parathyroid hormone is the most likely factor enhancing the repeated cycling of 25(OH)D between skeletal muscle and blood. This mechanism appears to have evolved to maintain an adequate vitamin D status in winter.
Summary
The recommended level for serum 25‐hydroxyvitamin D (25(OH)D) in infants, children, adolescents and during pregnancy and lactation is ≥ 50 nmol/L. This level may need to be 10–20 nmol/L ...higher at the end of summer to maintain levels ≥ 50 nmol/L over winter and spring.
Sunlight is the most important source of vitamin D. The US recommended dietary allowance for vitamin D is 600 IU daily in children aged over 12 months and during pregnancy and lactation, assuming minimal sun exposure.
Risk factors for low vitamin D are: lack of skin exposure to sunlight, dark skin, southerly latitude, conditions affecting vitamin D metabolism and storage (including obesity) and, for infants, being born to a mother with low vitamin D and exclusive breastfeeding combined with at least one other risk factor.
Targeted measurement of 25(OH)D levels is recommended for infants, children and adolescents with at least one risk factor for low vitamin D and for pregnant women with at least one risk factor for low vitamin D at the first antenatal visit.
Vitamin D deficiency can be treated with daily low‐dose vitamin D supplements, although barriers to adherence have been identified. High‐dose intermittent vitamin D can be used in children and adolescents. Treatment should be paired with health education and advice about sensible sun exposure. Infants at risk of low vitamin D should be supplemented with 400 IU vitamin D3 daily for at least the first year of life.
There is increasing evidence of an association between low vitamin D and a range of non‐bone health outcomes, however there is a lack of data from robust randomised controlled trials of vitamin D supplementation.
Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated ...through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.
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